Irreversible inhibitors of tyrosine kinases

ABSTRACT

The present invention provides compounds that are irreversible inhibitors of tyrosine kinases. Also provided is a method of treating cancer, restenosis, atherosclerosis, endometriosis, and psoriasis and a pharmaceutical composition that comprises a compound that is an irreversible inhibitor of tyrosine kinases.

This is a divisional of co-pending Ser. No. 09/155,501 filed on Jun. 8,1999, which is a 371 of PCT/US97/05778, filed Apr. 8, 1997, which claimsthe benefit of Provisional application Ser. No. 60/015,351, filed Apr.12, 1996.

FIELD OF THE INVENTION

This invention relates to compounds that are irreversible inhibitors oftyrosine kinases. This invention also relates to a method of treatingcancer, atherosclerosis, restenosis, endometriosis, and psoriasis, andto a pharmaceutical composition that comprises a compound that is anirreversible inhibitor of tyrosine kinases.

BACKGROUND OF THE INVENTION

Cancer has been viewed as a disease of the intracellular signallingsystem, or signal transduction mechanism. Cells receive instructionsfrom many extracellular sources, instructing them to either proliferateor not to proliferate. The purpose of the signal transduction system isto receive these and other signals at the cell surface, get them intothe cell, and then pass the signals on to the nucleus, the cytoskeleton,and transport and protein synthesis machinery.

The most common cause of cancer is a series of defects, either in theseproteins, when they are mutated, or in the regulation of the quantity ofthe protein in the cell such that it is over or under produced. Mostoften, there are key lesions in the cell which lead to a constitutivestate whereby the cell nucleus receives a signal to proliferate, whenthis signal is not actually present. This can occur through a variety ofmechanisms. Sometimes the cell may start to produce an authentic growthfactor for its own receptors when it should not, the so-called autocrineloop mechanism. Mutations to the cell surface receptors, which usuallysignal into the cell by means of tyrosine kinases, can lead toactivation of the kinase in the absence of ligand, and passing of asignal which is not really there. Alternatively, many surface kinasescan be overexpressed on the cell surface leading to an inappropriatelystrong response to a weak signal. There are many levels inside the cellat which mutation or overexpression can lead to the same spurious signalarising in the cell, and there are many other kinds of signallingdefects involved in cancer. This invention touches upon cancers whichare driven by the three mechanisms just described, and which involvecell surface receptors of the epidermal growth factor receptor tyrosinekinase family (EGFR). This family consists of the EGF receptor (alsoknown as Erb-B1), the Erb-B2 receptor, and its constitutively activeoncoprotein mutant Neu, the Erb-B3 receptor and the Erb-B4 receptor.Additionally, other biological processes driven through members of theEGF family of receptors can also be treated by compounds of theinvention described below.

The EGFR has as its two most important ligands Epidermal Growth Factor(EGF) and Transforming Growth Factor alpha (TGFalpha). The receptorsappear to have only minor functions in adult humans, but are apparentlyimplicated in the disease process of a large portion of all cancers,especially colon and breast cancer. The closely related Erb-B2, Erb-B3,and Erb-B4 receptors have a family of Heregulins as their major ligands,and receptor overexpression and mutation have been unequivocallydemonstrated as the major risk factor in poor prognosis breast cancer.Additionally, it has been demonstrated that all four of the members ofthis family of receptors can form heterodimeric signalling complexeswith other members of the family, and that this can lead to synergistictransforming capacity if more than one member of the family isoverexpressed in a malignancy. Overexpression of more than one familymember has been shown to be relatively common in human malignancies.

In addition to cancer, restenosis is also a disease in which undesiredcellular proliferation occurs. Restenosis involves the proliferation ofvascular smooth muscle cells. Restenosis is a major clinical problemassociated with coronary angioplasty and other medical procedures.Restenosis generally occurs within about 0 to 6 months in about 30% to50% of patients who undergo balloon angioplasty to clear cloggedcoronary arteries in an effort to treat heart disease due to occludedarteries. The resulting restenosis causes substantial patient morbidityand health care expense.

The process of restenosis is initiated by injury of the blood vessel,including arteries and veins, with the subsequent release ofthrombogenic, vasoactive, and mitogenic factors. Endothelial and deepvessel injury leads to platelet aggregation, thrombus formation,inflammation, and activation of macrophages and smooth muscle cells.These events induce the production of and release of growth factors andcytokines, which in turn may promote their own synthesis and releasefrom target cells. Thus, a self-perpetuating process involving growthfactors such as EGF, platelet derived growth factor (PDGF) or fibroblastgrowth factor (FGFs) is initiated. Thus, it would be useful to haveirreversible inhibitors of signal transduction pathways, particularly oftyrosine kinases like EGF, PDGF, FGF, or src tyrosine kinases.

The proliferative skin disease psoriasis has no good cure at present. Itis often treated by anticancer agents such as methotrexate, which havevery serious side effects, and which are not very effective at thetoxicity limited doses which have to be used. It is believed that TGFalpha is the major growth factor overproduced in psoriasis, since 50% oftransgenic mice which over express TGF alpha develop psoriasis. Thissuggests that a good inhibitor of EGFR signalling could be used asantipsoriatic agent, preferably, but not necessarily, by topical dosing.

It is especially advantageous to have irreversible tyrosine kinaseinhibitors when compared to reversible inhibitors, because irreversibleinhibitors can be used in prolonged suppression of the tyrosine kinase,limited only by the normal rate of receptor resynthesis, also calledturnover.

Additional information on the role of src tyrosine kinases in biologicalprocesses relating to cancer and restenosis can be found in thefollowing documents, which are all hereby incorporated by reference.

Benjamin C. W. and Jones D. A, Platelet-Derived Growth Factor StimulatesGrowth Factor Receptor Binding Protein-2 Association With Src InVascular Smooth Muscle Cells, JBC, 1994;269:30911-30916.

Kovalenko M., et al., Selective Platelet-Derived Growth Factor ReceptorKinase Blockers Reverse Cis-transformation, Cancer Res,1994;54:6106-6114.

Schwartz R. S., et al., The Restenosis Paradigm Revisted: An AlternativeProposal for Cellular Mechanisms, J Am Coll Cardiol, 1992;20:1284-1293.

Libby P., et al., Cascade Model for Restenosis—A Special Case ofAtherosclerosis Progression, Circulation, 1992;86:47-52.

Additional information on the role of EGF tyrosine kinases in biologicalprocesses relating to cancer and restenosis can be found in thefollowing document which is hereby incorporated by reference.

Jonathan Blay and Morley D. Hollenberg, Heterologous Regulation Of EGFReceptor Function In Cultured Aortic Smooth Muscle Cells, Eur JPharmacol, Mol Pharmacol Sect, 1989;172(1):1-7.

Information that shows that antibodies to EGF or EGFR show in vivoantitumor activity can be found in the following documents which arehereby incorporated by reference.

Modjtahedi H., Eccles S., Box G., Styles J., Dean C, Immunotherapy OfHuman Tumour Xenografts Overexpressing The EGF Receptor With RatAntibodies That Block Growth Factor-Receptor Interaction, Br J Cancer,1993;67:254-261.

Kurachi H., Morishige K. I., Amemiya K., Adachi H., Hirota K., MiyakeA., Tanizawa O, Importance Of Transforming Growth Factor Alpha/EpidermalGrowth Factor Receptor Autocrine Growth Mechanism In An Ovarian CancerCell Line In Vivo, Cancer Res, 1991;51:5956-5959.

Masui H., Moroyama T., Mendelsohn J, Mechanism Of Antitumor Activity InMice For Anti-Epidermal Growth Factor Receptor Monoclonal AntibodiesWith Different Isotypes, Cancer Res, 1986;46:5592-5598.

Rodeck U., Herlyn M., Herlyn D., Molthoff C., Atkinson B., Varello M.,Steplewski Z., Koprowski H., Tumor Growth Modulation By A MonoclonalAntibody To The Epidermal Growth Factor Receptor: ImmunologicallyMediated And Effector Cell-Independent Effects, Cancer Res,1987;47:3692-3696.

Guan E., Zhou T., Wang J., Huang P., Tang W., Zhao M., Chen Y., Sun Y,Growth Inhibition Of Human Nasopharyngeal Carcinoma In Athymic Mice ByAnti-Epidermal Growth Factor Receptor Monoclonal Antibodies, Internat JCell Clon, 1989;7:242-256.

Masui H., Kawamoto T., Sato J. D., Wolf B., Sato G., Mendelsohn J,Growth Inhibition Of Human Tumor Cells In Athymic Mice By Anti-EpidermalGrowth Factor Receptor Monoclonal Antibodies, Cancer Res,1984;44:1002-1007.

In addition, the following documents show the antitumor activity ofprotein tyrosine kinase inhibitors. The documents are herebyincorporated by reference.

Buchdunger E., Trinks U., Mett H., Regenass U., Muller M., Meyer T.,McGlynn E., Pinna L. A., Traxler P., Lydon N. B.4,5-Dianilinophthalimide: A Protein Tyrosine Kinase Inhibitor WithSelectivity For The Epidermal Growth Factor Receptor Signal TransductionPathway And Potent In Vivo Antitumor Activity, Proc Natl Acad Sci USA,1994;91:2334-2338.

Buchdunger E., Mett H., Trinks U., Regenass U., Muller M., Meyer T.,Beilstein P., Wirz B., Schneider P., Traxler P., Lydon N.4,5-Bis(4-Fluoroanilino)Phthalimide: A Selective Inhibitor Of TheEpidermal Growth Factor Receptor Signal Transduction Pathway With PotentIn Vivo Mdd Antitumor Activity, Clinical Cancer Research,1995;1:813-821.

Compounds that are reversible inhibitors of tyrosine kinases have beendescribed in U.S. Pat. Nos. 5,457,105, 5,475,001, and 5,409,930 and inPCT publication Numbers WO 9519774 and WO 9519970. The presentlydisclosed compounds, which are structurally different from the tyrosinekinase inhibitors described in the above-identified documents, areirreversible inhibitors of tyrosine kinases.

SUMMARY OF THE INVENTION

The present invention provides compounds having the Formula I

wherein

X is —D—E—F and Y is —SR⁴, halogen, —OR —NHR³, or hydrogen, or X is—SR⁴, halogen, —OR⁴, —NHR³, or hydrogen, and Y is —D—E—F;

provided that when E is

D is not

 R¹ is hydrogen, halogen, or C₁-C₆ alkyl;

R², R³, and R⁴ are independently hydrogen, C₁-C₆ alkyl,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)-imidazoyl,—(CH₂)_(n)—N-morpholino, —(CH₂)_(n)—N-thiomorpholino,—(CH₂)_(n)—N-hexahydroazepine or substituted C₁-C₆ alkyl, wherein thesubstituents are selected from —OH, —NH₂, or

 A and B are independently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄-(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)—N-pyridyl, —(CH₂)_(n)-imidazoyl, or —(CH₂)_(n)—N-imidazoyl;

Z¹, Z², or Z³ are independently hydrogen, halogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₁-C₆ alkoxy, C₃-C₈ cycloalkoxy, nitro, C₁-C₆perfluoroalkyl, hydroxy, C₁-C₆ acyloxy, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NH(C₃-C₈ cycloalkyl), —N(C₃-C₈ cycloalkyl)₂, hydroxymethyl,C₁-C₆ acyl, cyano, azido, C₁-C₆ thioalkyl, C₁-C₆ sulfinylalkyl, C₁-C₆sulfonylalkyl, C₃-C₈ thiocycloalkyl, C₃-C₈ sulfinylcycloalkyl, C₃-C₈sulfonylcycloalkyl, mercapto, C₁-C₆ alkoxycarbonyl, C₃-C₈cycloalkoxycarbonyl, C₂-C₄ alkenyl, C₄-C₈ cycloalkenyl, or C₂-C₄alkynyl;

R⁵ is hydrogen, halogen, C₁-C₆-perfluoroalkyl, 1,1-difluoro(C₁-C₆)alkyl,C₁-C₆alkyl, —(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)-piperazinyl,—(CH₂)_(n)-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino,

 —CH═CH—(C₁-C₆)alkyl, —(CH₂)_(n)—N-hexahydroazepine, —(CH₂)_(n)NH₂,—(CH₂)_(n)NH(C₁-C₆alkyl), —(CH₂)_(n)N(C₁-C₆alkyl)₂, -1-oxo(C₁-C₆)alkyl,carboxy, (C₁-C₆)alkyloxycarbonyl, N—(C₁-C₆)alkylcarbamoyl, phenyl orsubstituted phenyl, wherein the substituted phenyl can have from one tothree substituents independently selected from Z¹, Z², Z³ or amonocyclic heteroaryl group, and each C₁-C₆ alkyl group above in R⁵ canbe substituted with —OH, —NH₂ or —NAB, where A and B are as definedabove, R⁶ is hydrogen or C₁-C₆ alkyl; R¹³ is hydrogen or halogen; and

n is 1 to 4, p is 0 or 1, and the pharmaceutically acceptable salts,esters, amides, and prodrugs thereof.

In a preferred embodiment of the compound of Formula I, Z¹ and Z² arehydrogen, and Z³ is a halogen.

In a more preferred embodiment of the compounds of Formula I, Z³ isbromine.

In another more preferred embodiment of the compounds of Formula I, thebromine is located at the 3 or meta position of the phenyl ring.

In another preferred embodiment, Z¹ is hydrogen, Z² is F, and Z³ is Cl.

In another more preferred embodiment, Z₁ is hydrogen, Z² is F, and Z³ isCl, wherein Z² is located at the 4 position, and Z³ is located at the 3position of the phenyl ring.

In another preferred embodiment of the compounds of Formula I, X is

and Y is hydrogen, or X is hydrogen, and Y is

In another preferred embodiment of the compounds of Formula I, Y is—D—E—F, and —D—E—F is

In another preferred embodiment of the compounds of Formula I, X is—D—E—F, and —D—E—F is

In another preferred embodiment of the compounds of Formula I, R² ishydrogen.

In another preferred embodiment of the compounds of Formula I, Y is—D—E—F and X is —O(CH₂)_(n)-morpholino.

In another preferred embodiment of the compounds of Formula I, R⁵ iscarboxy, (C₁-C₆ alkyl)oxycarbonyl or C₁-C₆ alkyl.

In another preferred embodiment of the compounds of Formula I, Y is—D—E—F and X is —O(CH₂)_(n)morpholino.

In another preferred embodiment of the compounds of Formula I, Y is—D—E—F and X is —O—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl].

In another preferred embodiment of the compounds of Formula I, Y is—D—E—F and X is —O—(CH₂)_(n)-imidazoyl.

In another embodiment, the present invention provides compounds havingthe Formula II

wherein

Q is

 p is 0 or 1;

X is —D—E—F, and Y is —SR⁴, —OR⁴, —NHR³ or hydrogen, or X is —SR⁴, —OR⁴,—NHR³ or hydrogen, and Y is —D—E—F;

provided that when E is

D is not

 R¹ is hydrogen, halogen, or C₁-C₆ alkyl;

R², R³, and R⁴ are independently hydrogen, C₁-C₆ alkyl,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)-imidazoyl,—(CH₂)_(n)—N-morpholino, —(CH₂)_(n)—N-thiomorpholino,—(CH₂)_(n)—N-hexahydroazepine or substituted C₁-C₆ alkyl, wherein thesubstituents are selected from —OH, —NH₂, or

 A and B are independently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)—N-pyridyl, —(CH₂)_(n)-imidazoyl, or —(CH₂)_(n)—N-imidazoyl;

E¹, E², and E³ are independently halogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₁-C₆ alkoxy, C₃-C₈ cycloalkoxy, nitro, C₁-C₆ perfluoroalkyl, hydroxy,C₁-C₆ acyloxy, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NH(C₃-C₈cycloalkyl), —N(C₃-C₈ cycloalkyl)₂, hydroxymethyl, C₁-C₆ acyl, cyano,azido, C₁-C₆ thioalkyl, C₁-C₆ sulfinylalkyl, C₁-C₆ sulfonylalkyl, C₃-C₈thiocycloalkyl, C₃-C₈ sulfinylcycloalkyl, C₃-C₈ sulfonylcycloalkyl,mercapto, C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkoxycarbonyl, C₂-C₄alkenyl, C₄-C₈ cycloalkenyl, or C₂-C₄ alkynyl;

R⁵ is hydrogen, halogen, C₁-C₆-perfluoroalkyl, 1,1-difluoro(C₁-C₆)alkyl,C₁-C₆ alkyl, —(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)-piperazinyl,—(CH₂)_(n)-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino,

 —CH═CH—(C₁-C₆)alkyl, —(CH₂)_(n)—N-hexahydroazepine, —(CH₂)_(n)NH₂,—(CH₂)_(n)NH(C₁-C₆ alkyl), —(CH₂)_(n)N(C₁-C₆ alkyl)₂,-1-oxo(C₁-C₆)alkyl, carboxy, (C₁-C₆)alkyloxycarbonyl,N—(C₁-C₆)alkylcarbamoyl, phenyl or substituted phenyl, wherein thesubstituted phenyl can have from one to three substituents independentlyselected from Z¹, Z², Z³ or a monocyclic heteroaryl group, and eachC₁-C₆ alkyl group can be substituted with —OH, —NH₂ or —NAB, where A andB are as defined above, R⁶ is hydrogen or C₁-C₆ alkyl; and

n is 1 to 4, p is 0 and 1, and the pharmaceutically acceptable salts,esters, amides, and prodrugs thereof.

In a preferred embodiment of the compounds of Formula II, E¹ and E² arehydrogen, and E³ is a halogen.

In a more preferred embodiment of the compounds of Formula II, thehalogen is bromine.

In another more preferred embodiment of the compounds of Formula II, thebromine is located at the three or meta position of the phenyl ring.

In another more preferred embodiment, E¹ is hydrogen, E² is chlorine,and E³ is fluorine.

In another preferred embodiment of the compounds of Formula II, Q is

In another preferred embodiment of the compounds of Formula II, Q is

In another preferred embodiment of the compounds of Formula II, Q is

In another preferred embodiment of the compounds of Formula II, Q is

In another preferred embodiment of the compounds of Formula II, X is

In another preferred embodiment of the compounds of Formula II, X is

In another embodiment, the present invention provides compounds havingthe Formula III

wherein Q is

p is 0 or 1;

X is —D—E—F, and Y is —SR⁴, —OR⁴, —NHR³ or hydrogen, or X is —SR⁴, —OR⁴,—NHR³ or hydrogen, and Y is —D—E—F;

D is

 or absent;

 provided that when E is

 D is not

 R¹ is hydrogen, halogen, or C₁-C₆ alkyl;

R², R³, and R⁴ are independently hydrogen, C₁-C₆ alkyl,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)-imidazoyl,—(CH₂)_(n)—N-morpholino, —(CH₂)_(n)—N-thiomorpholino,—(CH₂)_(n)—N-hexahydroazepine or substituted C₁-C₆ alkyl, wherein thesubstituents are selected from —OH, —NH₂, or

 A and B are independently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)—N-pyridyl, —(CH₂)_(n)-imidazoyl, or —(CH₂)_(n)—N-imidazoyl;

E¹, E², and E³ are independently halogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₁-C₆ alkoxy, C₃-C₈ cycloalkoxy, nitro, C₁-C₆ perfluoroalkyl, hydroxy,C₁-C₆ acyloxy, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NH(C₃-C₈cycloalkyl), —N(C₃-C₈ cycloalkyl)₂, hydroxymethyl, C₁-C₆ acyl, cyano,azido, C₁-C₆ thioalkyl, C₁-C₆ sulfinylalkyl, C₁-C₆ sulfonylalkyl, C₃-C₈thiocycloalkyl, C₃-C₈ sulfinylcycloalkyl, C₃-C₈ sulfonylcycloalkyl,mercapto, C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkoxycarbonyl, C₂-C₄alkenyl, C₄-C₈ cycloalkenyl, or C₂-C₄ alkynyl;

R⁵ is hydrogen, halogen, C₁-C₆-perfluoroalkyl, 1,1-difluoro(C₁-C₆)alkyl,C₁-C₆ alkyl, —(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)-piperazinyl,—(CH₂)_(n)-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino,

 —CH═CH—(C₁-C₆)alkyl, —(CH₂)_(n)—N-hexahydroazepine, —(CH₂)_(n)NH₂,—(CH₂)_(n)NH(C₁-C₆ alkyl), —(CH₂)_(n)N(C₁-C₆ alkyl)₂,-1-oxo(C₁-C₆)alkyl, carboxy, (C₁-C₆)alkyloxycarbonyl,N—(C₁-C₆)alkylcarbamoyl, phenyl or substituted phenyl, wherein thesubstituted phenyl can have from one to three substituents independentlyselected from Z¹, Z², Z³ or a monocyclic heteroaryl group, and eachC₁-C₆ alkyl group can be substituted with —OH, —NH₂ or —NAB, where A andB are as defined above, R⁶ is hydrogen or C₁-C₆ alkyl; and

n is 1 to 4, and the pharmaceutically acceptable salts, esters, amides,and prodrugs thereof.

In another preferred embodiment of the compounds of Formula III, Q is

In another preferred embodiment of the compounds of Formula III, Q is

In another preferred embodiment of the compounds of Formula III, X is

In another preferred embodiment of the compounds of Formula III, E¹ andE² are hydrogen and E³ is bromine.

In another preferred embodiment of the compounds of Formula III, E¹ ishydrogen, E² is chlorine, and E³ is fluorine.

In another preferred embodiment of the compounds of Formula III, X is

In another preferred embodiment, Q is a 6-substitutedbenzothieno[3,2-d]pyrmid-4-yl.

The present invention also provides a pharmaceutically acceptablecomposition that comprises a compound of Formula I, II, or III.

The present invention also provides a method of treating cancer, themethod comprising administering to a patient having cancer atherapeutically effective amount of a compound of Formula I, II, or III.

The present invention also provides a method of treating or preventingrestenosis, the method comprising administering to a patient havingrestenosis or at risk of having restenosis, a therapeutically effectiveamount of a compound of Formula I, II, or III.

The present invention also provides a method of treating psoriasis, themethod comprising administering to a patient having psoriasis atherapeutically effective amount of a compound of Formula I, II, or III.

The present invention also provides a method of treatingatherosclerosis, the method comprising administering to a patient havingatherosclerosis a therapeutically effective amount of a compound ofFormula I, II, or III.

The present invention also provides a method of treating endometriosis,the method comprising administering to a patient having endometriosis atherapeutically effective amount of a compound of Formula I, II, or III.

The present invention also provides a method of irreversibly inhibitingtyrosine kinases, the method comprising administering to a patient inneed of tyrosine kinase inhibition a tyrosine kinase inhibiting amountof a compound of Formula I, II or III.

The present invention provides the following compounds:

N-[4-(3-Bromo-phenylamino)-pyrido[4,3-d]-pyrimidin-7-yl]-N-(3-morpholin-4-yl-propyl)-acrylamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]-pyrimidin-6-yl]-N-(3-morpholin-4-yl-propyl)-acrylamide;

N-[4-(3-Bromo-phenylamino)-quinazolin-7-yl]-acrylamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-7-yl]-N-[3-morpholinopropyl]acrylamide;

3-[4-(3-Bromo-phenylamino)-quinazolin-7-yl-carbamoyl]-acrylic acid;

3-[4-(3-Bromo-phenylamino)-quinazolin-7-yl-carbamoyl]-acrylic acid ethylester;

But-2-enoic acid[4-(3-bromo-phenylamino)-quinazolin-7-yl]-amide;

N-[4-(3-Bromo-phenylamino)-6-(3-morpholin-4-yl-propylamino)-quinazolin-7-yl]-acrylamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-acrylamide;

N-[4-(3-Methyl-phenylamino)-quinazolin-7-yl]-acrylamide;

N-[4-(3-Chloro-phenylamino)-quinazolin-7-yl]-acrylamide;

N-[4-(3-Bromo-phenylamino)-quinazolin-7-yl]-methacrylamide;

N-[4-(3-Bromo-phenylamino)-quinazolin-7-yl]-ethenylsulfonamide;

N-[4-[(3-Chlorophenyl)amino]quinazolin-6-yl]-acrylamide;

N-[4-[(3-Methylphenyl)amino]quinazolin-6-yl]-acrylamide;

N-[4-[(3-(Trifluoromethyl)phenyl)amino]quinazolin-6-yl]acrylamide;

N-[4-[(3-Bromophenyl)amino]-7-[3-(4-morpholino)-propoxy]quinazolin-6-yl]acrylamide;

N-[4-[(3-Methylphenyl)amino]-7-[3-(4-morpholino)-propoxy]quinazolin-6-yl]acrylamide;

N-[4-[(3-Methylphenyl)amino]-7-[3-(4,N-methyl-1,N-piperazino)propoxy]quinazolin-6-yl]acrylamide;

N-[4-[(3-Bromophenyl)amino]-7-[3-(4,N-methyl-1,N-piperazino)propoxy]quinazolin-6-yl]acrylamide;

N-[4-[(3-Bromophenyl)amino]-7-[3-(1,N-imidazyl)-propoxy]quinazolin-6-yl]acrylamide;

N-[4-[(3-Bromophenyl)amino]-7-[4-(N,N-dimethyl-amino)butoxy]quinazolin-6-yl]acrylamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-N-[3-morpholinopropyl]acrylamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-methacrylamide;

N-[4-(3-Bromo-phenylamino)-quinazolin-7-yl]-ethenylsulfonamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E-but-2-enamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-4,4,4-trifluoro-E-but-2-enamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]propynamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]but-2-ynamide;

N-[4-(3-Bromo-phenylamino)-pyrido[4,3-d]pyrimidin-7-yl]-acrylamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide;

N-[4-(3-Methyl-phenylamino)-pyrido[3,4-d]-pyrimidin-6-yl]-acrylamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-methylacrylamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-methacrylamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-ethenylsulfonamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,2-d]pyrimidin-6-yl]-acrylamide;

N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3,2-d]pyrimidin-8-yl]acrylamide;

N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3,2-d]pyrimidin-6-yl]acrylamide;

N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3,2-d]pyrimidin-7-yl]acrylamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]buta-2,3-dienamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E,4-oxopent-2-enamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E,4-ethoxy-4-oxobut-2-enamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]penta-2,4-dienamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-(2-(N,N-dimethylamino)ethyl)acrylamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]E-but-2-enamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]cinnamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-E,3-chloroacrylamide;

N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-propynamide;

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E,4-(3-(N,N-dimethylamino)propoxy-4-oxobut-2-enamidetris trifluoroacetate;

3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid (Z);

N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E,4-(3-(N,N-dimethylamino)propylamino-4-oxobut-2-enamide;

4-[(3-Bromo-phenyl)amino]-6-(ethenesulfonyl)-pyrido[3,4-d]pyrimidine;

1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-pyrrole-2,5-dione;

1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-prop-2-en-1-one;

Acrylic acid 4-(3-bromo-phenylamino)-quinazolin-6-yl ester;

MethylN-[4-[(3-bromophenyl)amino]-P-ethenyl-pyrido[3,4-d]pyrimidin-6-yl]phosphonamidate;

Acrylic acid 4-(3-bromo-phenylamino)-quinazolin-7-yl ester;

1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-but-3-en-2-one;

Acrylic acid 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ylester;

N-[4-(3-Bromo-phenylamino)-7-(3-morpholin-4-yl-propoxy)-pyrido[3,2-d]pyrimidin-6-yl]-acrylamide;

Penta-2,3-dienoic acid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

Propa-1,2-diene-1-sulfonicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

MethylN-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-P-(1,2-propadienyl)phosphonamidate;

N-[1-(3-Bromo-phenylamino)-9H-2,4,9-triaza-fluoren-7-yl]-acrylamide;

N-[4-(3-Bromo-phenylamino)-9H-1,3,9-triaza-fluoren-6-yl]-acrylamide;

N-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-acrylamide;

N-(4-Phenylmethylamino-quinazolin-6-yl)-acrylamide;

(S)-N-[4-(1-Phenyl-ethylamino)-quinazolin-6-yl]-acrylamide;

(R)-N-[4-(1-Phenyl-ethylamino)-quinazolin-6-yl]-acrylamide;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide(3-dimethylamino-propyl)-amide;

N-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide;

N-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-methyl-acrylamide;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-dimethylamino-propyl)-amide;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;

4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Dimethylamino-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-(4-Methyl-piperazin-1-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-(4-methyl-piperazin-1-yl)-ethyl ester;

4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-(imidazol-1-yl)-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide];

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];

4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-morpholin-4-yl-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-{[3-4-methyl-piperazin-1-yl)-propyl]-amide};

(3-Chloro-4-fluoro-phenyl)-{6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl)-pyrido[3,4-d]pyrimidin-4-yl}-amine;

(3-Chloro-4-fluoro-phenyl)-(6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl}-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(3-Chloro-4-fluoro-phenyl)-[6-(5-morpholin-4-yl-pent-1-ene-1-sulfonyl)-pyrido[3,4-d]pyrimidin-4-yl]-amine;

(3-Chloro-4-fluoro-phenyl)-(6-ethenesulfinyl-pyrido[3,4-d]pyrimidin-4-yl]-amine;

3-[4-(1-Phenyl-ethylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid2-morpholin-4-yl-ethyl ester;

But-2-enedioic acid(4-imidazol-1-yl-butyl)-amide[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

4-[4-(1-Phenyl-ethylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoic acid3-diethylamino-propyl ester;

Pent-2-enedioic acid 5-{[2-(4-methyl-piperazin-1-yl)-ethyl]-amide}1-{[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide};

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

7-Imidazol-1-yl-hept-2-ynoicacid[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

But-2-enedioicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-dimethylamino-propyl)-amide;

But-2-enedioicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;

4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-hept-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Dimethylamino-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-(4-Methyl-piperazin-1-yl)-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-(4-methyl-piperazin-1-yl)-ethyl ester;

4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-imidazol-1-yl-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide];

Pent-2-enedioic acid1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];

4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-morpholin-4-yl-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-{[3-(4-methyl-piperazin-1-yl)-propyl]-amide};

(3-Bromo-phenyl)-{6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;

(3-Bromo-phenyl)-[6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl}-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(3-Bromo-phenyl)-[6-(5-morpholin-4-yl-pent-1-ene-1-sulfonyl)-pyrido[3,4-d]pyrimidin-4-yl]-amine;

(3-Bromo-phenyl)-(6-ethenesulfinyl-pyrido[3,4-d]pyrimidin-4-yl)-amine;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide(3-dimethylamino-propyl)-amide;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;

4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

5-Dimethylamino-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

5-(4-Methyl-piperazin-1-yl)-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide];

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];

4-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoicacid 2-morpholin-4-yl-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide}5-{[3-(4-methyl-piperazin-1-yl)-propyl]-amide};

(3-Chloro-4-fluoro-phenyl)-{6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl]-quinazolin-4-yl}-amine;

(3-Chloro-4-fluoro-phenyl)-(6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl}-quinazolin-4-yl)-amine;

But-2-enedioicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide(3-dimethylamino-propyl)-amide;

But-2-enedioicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;

4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-hept-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

5-Dimethylamino-pent-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

5-(4-Methyl-piperazin-1-yl)-pent-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

4-[4-(3-Bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoic acid2-(4-methyl-piperazin-1-yl)-ethyl ester;

4-[4-(3-Bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoic acid2-imidazol-1-yl-ethyl ester;

Pent-2-enedioic acid 1-{[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide];

Pent-2-enedioic acid 1-{[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];

4-[4-(3-Bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoic acid2-morpholin-4-yl-ethyl ester;

Pent-2-enedioic acid 1-{[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide}5-{[3-(4-methyl-piperazin-1-yl)-propyl]-amide};

3-[4-(1-Phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-acrylicacid 2-morpholin-4-yl-ethyl ester;

But-2-enedioicacid(4-imidazol-1-yl-butyl)-amide[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4-[4-(1-Phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 3-diethylamino-propyl ester;

Pent-2-enedioic acid 5-{[2-(4-methyl-piperazin-1-yl)-ethyl]-amide}1-{[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide};

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Imidazol-1-yl-hept-2-ynoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

But-2-enedioicacid[4-(3-chloro-4-fluorophenylamino)-7-fluoroquinazolin-6-yl]amide(3-dimethylaminopropyl)amide;

But-2-enedioicacid[7-chloro-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl]amide(3-dimethylaminopropyl)amide;

N-[4-[3-(Bromophenyl)amino]-5-fluoro-7-[3-(4-morpholino)propoxy]quinazolin-6-yl]acrylamide;and

N-[4-[(3-(Chloro-4-fluorophenyl)amino]-5-fluoro-7-(1,N-imidazoyl)propoxy]quinazolin-6-yl]acrylamide.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds having the Formula I

wherein

X is —D—E—F, and Y is —SR⁴, halogen, —OR⁴, —NHR³, or hydrogen, or X is—SR⁴, halogen, —OR⁴, —NHR³, or hydrogen, and Y is —D—E—F;

 or absent;

 provided that when E is

 D is not

 R¹ is hydrogen, halogen, or C₁-C₆ alkyl;

R², R³, and R⁴ are independently hydrogen, C₁-C₆ alkyl,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)-imidazoyl,—(CH₂)_(n)—N-morpholino, —(CH₂)_(n)—N-thiomorpholino,—(CH₂)_(n)—N-hexahydroazepine or substituted C₁-C₆ alkyl, wherein thesubstituents are selected from —OH, —NH₂, or

 A and B are independently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆ alkyl)], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)—N-pyridyl, —(CH₂)_(n)-imidazoyl, or —(CH₂)_(n)—N-imidazoyl;

Z¹, Z², or Z³ are independently hydrogen, halogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₁-C₆ alkoxy, C₃-C₈ cycloalkoxy, nitro, C₁-C₆perfluoroalkyl, hydroxy, C₁-C₆ acyloxy, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —NH(C₃-C₈ cycloalkyl), —N(C₃-C₈ cycloalkyl)₂, hydroxymethyl,C₁-C₆ acyl, cyano, azido, C₁-C₆ thioalkyl, C₁-C₆ sulfinylalkyl, C₁-C₆sulfonylalkyl, C₃-C₈ thiocycloalkyl, C₃-C₈ sulfinylcycloalkyl, C₃-C₈sulfonylcycloalkyl, mercapto, C₁-C₆ alkoxycarbonyl, C₃-C₈cycloalkoxycarbonyl, C₂-C₄ alkenyl, C₄-C₈ cycloalkenyl, or C₂-C₄alkynyl;

R⁵ is hydrogen, halogen, C₁-C₆-perfluoroalkyl, 1,1-difluoro(C₁-C₆)alkyl,C₁-C₆ alkyl, —(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)-piperazinyl,—(CH₂)_(n)-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino,

 —CH═CH—(C₁-C₆)alkyl, —(CH₂)_(n)—N-hexahydroazepine, —(CH₂)_(n)NH₂,—(CH₂)_(n)NH(C₁-C₆ alkyl) —(CH₂)_(n)N(C₁-C₆ alkyl)₂, -1-oxo(C₁-C₆)alkyl,carboxy, (C₁-C₆)alkyloxycarbonyl, N—(C₁-C₆)alkylcarbamoyl, phenyl orsubstituted phenyl, wherein the substituted phenyl can have from one tothree substituents independently selected from Z¹, Z², Z³ or amonocyclic heteroaryl group, and each C₁-C₆ alkyl group can besubstituted with —OH, —NH₂ or —NAB, where A and B are as defined above,R⁶ is hydrogen or C₁-C₆ alkyl; R¹³ is hydrogen or halogen; and

n is 1 to 4, p is 0 or 1, and the pharmaceutically acceptable salts,esters, amides and prodrugs thereof.

In another embodiment, present invention also provides compounds havingthe Formula II

wherein Q is

p is 0 or 1;

X is —D—E—F and Y is —SR⁴, —OR⁴, —NHR³ or hydrogen, or X is —SR⁴, —OR⁴,—NHR³ or hydrogen, and Y is —D—E—F;

 or absent;

 provided that when E is

 D is not

 R¹ is hydrogen, halogen, or C₁-C₆ alkyl;

R², R³, and R⁴ are independently hydrogen, C₁-C₆ alkyl,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)-imidazoyl,—(CH₂)_(n)—N-morpholino, —(CH₂)_(n)—N-thiomorpholino,—(CH₂)_(n)—N-hexahydroazepine or substituted C₁-C₆ alkyl, wherein thesubstituents are selected from —OH, —NH₂, or

 A and B are independently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)—N-pyridyl, —(CH₂)_(n)-imidazoyl, or —(CH₂)_(n)—N-imidazoyl;

E¹, E², and E³ are independently halogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₁-C₆ alkoxy, C₃-C₈ cycloalkoxy, nitro, C₁-C₆ perfluoroalkyl, hydroxy,C₁-C₆ acyloxy, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NH(C₃-C₈cycloalkyl), —N(C₃-C₈ cycloalkyl)₂, hydroxymethyl, C₁-C₆ acyl, cyano,azido, C₁-C₆ thioalkyl, C₁-C₆ sulfinylalkyl, C₁-C₆ sulfonylalkyl, C₃-C₈thiocycloalkyl, C₃-C₈ sulfinylcycloalkyl, C₃-C₈ sulfonylcycloalkyl,mercapto, C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkoxycarbonyl, C₂-C₄alkenyl, C₄-C₈ cycloalkenyl, or C₂-C₄ alkynyl;

R⁵ is hydrogen, halogen, C₁-C₆-perfluoroalkyl, 1,1-difluoro(C₁-C₆)alkyl,C₁-C₆ alkyl, —(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)-piperazinyl,—(CH₂)_(n)-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino,

 —CH═CH—(C₁-C₆)alkyl, —(CH₂)_(n)—N-hexahydroazepine, —(CH₂)_(n)NH₂,—(CH₂)_(n)NH(C₁-C₆ alkyl), —(CH₂)_(n)N(C₁-C₆ alkyl)₂,-1-oxo(C₁-C₆)alkyl, carboxy, (C₁-C₆)alkyloxycarbonyl,N—(C₁-C₆)alkylcarbamoyl, phenyl or substituted phenyl, wherein thesubstituted phenyl can have from one to three substituents independentlyselected from Z¹, Z², Z³ or a monocyclic heteroaryl group, and eachC₁-C₆ alkyl group can be substituted with —OH, —NH₂ or —NAB, where A andB are as defined above, R⁶ is hydrogen or C₁-C₆ alkyl; and

n is 1 to 4, p is 0 or 1, and the pharmaceutically acceptable salts,esters, amides, and prodrugs thereof.

In another embodiment, the present invention provides compounds havingthe Formula III

wherein Q is

p is 0 or 1;

X is —D—E—F,and Y is —SR⁴, —OR⁴, —NHR³ or hydrogen, or X is —SR⁴, —OR⁴,—NHR³ or hydrogen, and Y is —D—E—F;

 or absent;

 provided that when E is

 D is not

 R¹ is hydrogen, halogen, or C₁-C₆ alkyl;

R², R³, and R⁴ are independently hydrogen, C₁-C₆ alkyl,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)-imidazoyl,—(CH₂)_(n)—N-morpholino, —(CH₂)_(n)—N-thiomorpholino,—(CH₂)_(n)—N-hexahydroazepine or substituted C₁-C₆ alkyl, wherein thesubstituents are selected from —OH, —NH₂, or

 A and B are independently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C_(l)-C₆ alkyl)], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)—N-pyridyl, —(CH₂)_(n)-imidazoyl, or —(CH₂)_(n)—N-imidazoyl;

E¹, E², and E³ are independently halogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₁-C₆ alkoxy, C₃-C₈ cycloalkoxy, nitro, C₁-C₆ perfluoroalkyl, hydroxy,C₁-C₆ acyloxy, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NH(C₃-C₈cycloalkyl), —N(C₃-C₈ cycloalkyl)₂, hydroxymethyl, C₁-C₆ acyl, cyano,azido, C₁-C₆ thioalkyl, C₁-C₆ sulfinylalkyl, C₁-C₆ sulfonylalkyl, C₃-C₈thiocycloalkyl, C₃-C₈ sulfinylcycloalkyl, C₃-C₈ sulfonylcycloalkyl,mercapto, C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkoxycarbonyl, C₂-C₄alkenyl, C₄-C₈ cycloalkenyl, or C₂-C₄ alkynyl;

R⁵ is hydrogen, halogen, C₁-C₆-perfluoroalkyl, 1,1-difluoro(C₁-C₆)alkyl,C₁-C₆ alkyl, —(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)-piperazinyl,—(CH₂)_(n)-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino,

 —CH═CH—(C₁-C₆)alkyl, —(CH₂)_(n)—N-hexahydroazepine, —(CH₂)_(n)NH₂,—(CH₂)_(n)NH(C₁-C₆ alkyl), —(CH₂)_(n)N(C₁-C₆ alkyl)₂,-1-oxo(C₁-C₆)alkyl, carboxy, (C₁-C₆)alkyloxycarbonyl,N—(C₁-C₆)alkylcarbamoyl, phenyl or substituted phenyl, wherein thesubstituted phenyl can have from one to three substituents independentlyselected from Z¹, Z², Z³ or a monocyclic heteroaryl group, and eachC₁-C₆ alkyl group can be substituted with —OH, —NH₂ or —NAB, where A andB are as defined above, R⁶ is hydrogen or C₁-C₆ alkyl; and

n is 1 to 4, and the pharmaceutically acceptable salts, esters, amides,and prodrugs thereof.

The term “alkyl” means a straight or branched chain hydrocarbon.Representative examples of alkyl groups are methyl, ethyl, propyl,isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl.

The term “alkoxy” means an alkyl group attached to an oxygen atom.Representative examples of alkoxy groups include methoxy, ethoxy,tert-butoxy, propoxy, and isobutoxy.

The term “halogen” includes chlorine, fluorine, bromine, and iodine.

The term “alkenyl” means a branched or straight chain hydrocarbon havingone or more carbon-carbon double bond.

The term “cycloalkyl” means a cyclic hydrocarbon. Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “cycloalkoxy” means a cycloalkyl group attached to an oxygenatom.

The term “perfluoroalkyl” means an alkyl group in which all the hydrogenatoms have been replaced by fluorine atoms.

The term “acyl” means a group derived from an organic acid by removal ofthe hydroxy group (—OH).

The term “acyloxy” means an acyl group attached to an oxygen atom.

The term “thioalkyl”, means an alkyl group attached to a sulfur atom.

The term “sulfinylalkyl” means a sulfinyl group attached to an alkylgroup.

The term “sulfonylalkyl” means a sulfonyl group attached to an alkylgroup.

The term “thiocycloalkyl” means a cycloalkyl group attached to a sulfuratom.

The term “sulfinylcycloalkyl” means a sulfinyl group attached to acycloalkyl group.

The term “sulfonylcycloalkyl” means a sulfonyl group attached to acycloalkyl group.

The term “mercapto” means a —SH group.

The term “alkoxycarbonyl” means an alkoxy group attached to a carbonylgroup.

The term “cycloalkoxycarbonyl” means a cycloalkyoxy group attached to acarbonyl group.

The term “cycloalkenyl” means a cyclic hydrocarbon containing one ormore carbon-carbon double bond.

The term “alkynyl”, means a hydrocarbon having one or more carbon-carbontriple bond.

The term “monocyclic heteroaryl” mean a heterocyclic aryl compoundhaving only one ring structure. The cyclic compound is aromatic andcontains one or more heteroatom. Examples of heteroatoms include, butare not limited to, nitrogen, oxygen, sulfur, and phosphorus. Examplesof monocyclic heteroaryl groups include, but are not limited to,pyridyl, thienyl, and imidazoyl.

The symbol “-” represents a covalent bond.

The compounds of Formulas I, II, and III are irreversible inhibitors oftyrosine kinases, particularly EGF tyrosine kinase. A therapeuticallyeffective amount of the compounds of Formula I, II, or III can beadministered to a patient having cancer or a patient having restenosisor at risk of having restenosis or a patient having psoriasis,atherosclerosis, or endometriosis. Those skilled in the art are readilyable to identify patients having cancer, restenosis, psoriasis,atherosclerosis, or endometriosis, and patients who are at risk ofdeveloping restenosis. The term “patient” means animals such as dogs,cats, cows, sheep, and also includes humans.

The compounds of the present invention can be administered to humans andanimals either orally, rectally, parenterally (intravenously,intramuscularly or subcutaneously), intracisternally, intravaginally,intraperitoneally, intravesically, locally (powders, ointments, ordrops), or as a buccal or nasal spray. The compounds can be administeredalone or as part of a pharmaceutically acceptable composition thatincludes pharmaceutically acceptable excipients. It is noted that morethan one compound of Formula I, II, III can be administered eitherconcurrently or sequentially.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (e) solution retarders, as for example paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearaite, solid polyethylene glycols, sodium lauryl sulfate, ormixtures thereof. In the case of capsules, tablets, and pills, thedosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft- and hard-filled gelatin capsules using such excipients as lactoseor milk sugar, as well as high molecular weight polyethylene-glycols,and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethyleneglycol or a suppository wax, which are solid atordinary temperatures but liquid at body temperature and therefore, meltin the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The term “pharmaceutically acceptable salts, esters, amides, andprodrugs” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medicaljudgement, suitable for use in contact with the tissues of patientswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “salts” refers to therelatively non-toxic, inorganic and organic acid addition salts ofcompounds of the present invention. These salts can be prepared in situduring the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with asuitable organic or inorganic acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate,glucoheptonate, lactobionate and laurylsulphonate salts, and the like.These may include cations based on the alkali and alkaline earth metals,such as sodium, lithium, potassium, calcium, magnesium, and the like, aswell as non-toxic ammonium, quaternary ammonium, and amine cationsincluding, but not limited to ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, ethylamine and the like (see, for example, S. M. Berge,et al., “Pharmaceutical Salts,” J Pharm Sci, 1977;66:1-19 which isincorporated herein by reference).

Examples of pharmaceutically acceptable, non-toxic esters of thecompounds of this invention include C₁-C₆ alkyl esters wherein the alkylgroup is a straight or branched chain. Acceptable esters also includeC₅-C₇ cycloalkyl esters as well as arylalkyl esters such as, but notlimited to benzyl. C₁-C₄ alkyl esters are preferred. Esters of thecompounds of the present invention may be prepared according toconventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁-C₆ alkyl amines and secondary C₁-C₆ dialkyl amines wherein the alkylgroups are straight or branched chain. In the case of secondary amines,the amine may also be in the form of a 5- or 6-membered heterocyclecontaining one nitrogen atom. Amides derived from ammonia, C₁-C₃ alkylprimary amines and C₁-C₂ dialkyl secondary amines are preferred. Amidesof the compounds of the invention may be prepared according toconventional methods.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulas, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated herein by reference.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 1,000 mg per day.For a normal human adult having a body weight of about 70 kg, a dosagein the range of about 0.01 to about 100 mg per kilogram of body weightper day is sufficient. The specific dosage used, however, can vary. Forexample, the dosage can depend on a number of factors including therequirements of the patient, the severity of the condition beingtreated, and the pharmacological activity of the compound being used.The determination of optimum dosages for a particular patient iswell-known to those skilled in the art.

The compounds of the present invention can exist in differentstereoisometric forms by virtue of the presence of asymmetric centers inthe compounds. It is contemplated that all stereoisometric forms of thecompounds as well as mixtures thereof, including racemic mixtures, formpart of this invention.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

It is intended that the compounds of Formula I, II, or III be eithersynthetically produced or biologically produced.

The following examples illustrate particular embodiments of theinvention and are not intended to limit the specification, including theclaims, in any manner.

GENERAL SYNTHETIC SCHEMES

Amine-Linked Alkylating Michael Acceptor Sidechains

The amine is acylated either by an acid in the presence of a couplingagent such as EDAC, or by an acid chloride. The amine in turn can bemade by reduction of the corresponding nitro compound, displacement of ahalogen by an amine or ammonia equivalent, or in the case ofpyrido[4,3-d]pyrimidines by direct incorporation during the synthesis.2-Haloalkylsulfonyl halides form vinyl sulfonamides when treated withthe aryl amine and excess tertiary amine base.

C/N means either a carbon or nitrogen atom is present at that location.--- means a bond or no bond.

Oxygen-Linked Alkylating Michael Acceptor Sidechains

The hydroxyl group is acylated either by an acid in the presence of acoupling agent such as EDAC, or by an acid chloride. The hydroxylcompound can in turn can be made by cleavage of the corresponding methylether. 3-Methylthioalkanoic acid or their acid chlorides can be used toacylate the oxygen followed by S-alkylation or oxidation and basic orthermal elimination.

Ar and R denote an aryl group and R denotes an organic group asexemplified herein.

Carbon-Linked Alkylating Michael Acceptor Sidechains

A Stille or Suzuki coupling can be used to couple the sidechain to anappropriately substitutedquinazoline/pyridopyrimidine/pyrimidinopyrimidine/tricycle. These inturn can be made as aryl halides by methods known in the art, or as aryltriflates by triflation of the hydroxyl compounds described above, asaryl stannanes by reaction of the abovementioned triflates withhexamethyl distannane, or as arylboronic acids by conversion of aryliodides to arylorgano-metallics, followed by treatment with borateesters and hydrolysis. Alternatively, aryl iodides can be converted tothe arylzinc species and coupled with activated halides.

Sulfur-Linked Alkylating Michael Acceptor Sidechains

Activated halides in pyridopyrimidines and pyrimidinopyrimidines can bedisplaced by suitable 2-hydroxythiolates, and these in turn can beoxidized to sulfones, and then water eliminated by treatment with mesylchloride and several equivalents of a base. For quinazolines, andclaimed tricycles, either an activated halogen especially fluorine canbe used in the sequence just described for pyridopyrimidines, or an aryliodide precursor can be metalated, quenched with sulfur or a suitablesulfur electrophilic progenitor and then the resultant aryl thiol usedto open a terminal epoxide, giving a 2-hydroxy thioether which can beconverted onto a vinyl sulfone by oxidation and water elimination asdescribed above.

Hydrazino-Linked Alkylating Michael Acceptor Sidechains

Activated halides in pyridopyrimidines and pyrimidinopyrimidines andappropriately substituted quinazolines can be displaced by a(N-alkyl)hydrazine. Alternatively, an amino-derivative of the desiredring nucleus can be diazotized, and then reduced to the hydrazine. Thedistal nitrogen of the hydrazine can then be acylated, sulfonylated orphosphorylated, by methods well-known to one skilled in the art.

Hydroxylamino-O-Linked Alkylating Michael Acceptor Sidechains

Activated halides in pyridopyrimidines and pyrimidinopyrimidines andappropriately substituted quinazolines can be displaced by a suitablyO-protected (N-alkyl) hydroxylamine. Alternatively, a nitro-derivativeof the desired ring nucleus can be synthesized, and then reduced to thehydroxylamine under appropriate mildly reducing conditions. The oxygenof the hydroxylamine can then be acylated, sulfonylated orphosphorylated, by methods well-known to one skilled in the art.

Methyleneamino-N-Linked Alkylating Michael Acceptor Sidechains

Activated halides in pyridopyrimidines and pyrimidinopyrimidines andappropriately substituted quinazolines can be displaced by cyanide,preferably in the presence of copper or nickel salt catalysis.Alternatively, an amino-derivative of the desired ring nucleus can bediazotized, and then converted to the nitrile as described above. Insome cases, the nitrile functionality can be incorporated into theheterocycle earlier in the synthesis, either as itself, or via acarboxylic acid or aldehyde, both of which can readily be turned intonitrile compounds by one skilled in the art. Reduction of the nitrile toa methyleneamine is followed by nitrogen acylation, sulfonylation orphosphorylation, by methods well-known to one skilled in the art.

Methyleneoxy-O-Linked Alkylating Michael Acceptor Sidechains

Hydroxymethyl compounds can be incorporated into appropriateheterocycles in many ways obvious to one skilled in the art. Forexample, iodoquinazolines may be carbonylated in a Heck reaction, andthen reduced with NaBH₄ to the desired precursor. Aminopyridopyrimidinesmay be diazotized, converted to the nitrile, partially reduced to animine, hydrolysed, and the resultant aldehyde reduced to hydroxymethyl.The oxygen of the hydroxymethyl can then be acylated, sulfonylated orphosphorylated, by methods well-known to one skilled in the art.

Ethano-Linked Alkylating Michael Acceptor Sidechains

Michael addition of a cuprate, derived via an organozincate from aniodoquinazoline, to a divinylketone, or appropriately mono-maskedderivative, followed by unmasking of the second unsaturatedfunctionality, if required, will give compounds of the desired type.Aldehydes derived from pyridopyrimidines or pyrimidopyrimidnes asdescribed above can be homologated to the desired compounds by a widevariety of techniques such as the one illustrated, by one skilled in theart.

Aminomethyl-C-Linked Alkylating Michael Acceptor Sidechains

Amino-heterocycles of the type described throughout this application canbe alkylated by various double bond-masked equivalents of1-bromobut-3-en-2-one, followed by unmasking of the unsaturation bymethods known to one skilled in the art.

Hydroxymethyl-C-Linked Alkylating Michael Acceptor Sidechains

Hydroxy-heterocycles made as described previously frommethoxy-heterocycles can be alkylated by various double bond-maskedequivalents of 1-bromobut-3-en-2-one, followed by unmasking of theunsaturation by methods known to one skilled in the art. Alternatively,alkylation of the phenol can be accomplished with chloroacetic acid,followed by conversion to an acyl chloride and Stille coupling of thatacyl halide with an appropriate alkenyl stannane.

Thiomethyl-C-Linked Alkylating Michael Acceptor Sidechains

Appropriate mercapto-heterocycles, made by displacement of activatedhalides on the heteroaromatic ring, can be alkylated by various doublebond-masked equivalents of 1-bromobut-3-en-2-one, followed by unmaskingof the unsaturation by methods known to one skilled in the art.Alternatively, alkylation of the thiol can be accomplished withchloroacetic acid, followed by conversion to an acyl chloride and Stillecoupling of that acyl halide with an appropriate alkenyl stannane.

EXAMPLE 1N-[4-(3-Bromo-phenylamino)-pyrido[4,3-d]pyrimidin-7-yl]-N-(3-morpholin-4-yl-propyl)-acrylamide

General Method A

N-[4-(3-Bromo-phenylamino)-pyrido[4,3-d]pyrimidin-7-yl]-N-(3-morpholin-4-yl-propyl)-acrylamidecan be made by acylation of7-amino-4-[(3-bromophenyl)amino]-pyrido[4,3-d]pyrimidine [J Med Chem,1995:3780] by methods familiar to one skilled in the art. For example,acylation with acrylic acid can be achieved through the use of astandard condensing agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDAC) or through theuse of acryloyl chloride and a tertiary base such as diisopropylethylamine as an acid scavenger.

N-alkylation of the acrylamides can then be achieved by methods familiarto one skilled in the art. For example, conversion of the amide to itsmonoanion by treatment with standard reagents such as sodium hydridefollowed by displacement on an appropriate halide such asN-(3-chloropropyl)morpholine or N-(4-chlorobutyl)morpholine affords thedesired alkylated amide.

General Method B

Alternatively,N-[4-(3-bromo-phenylamino)-pyrido[4,3-d]pyrimidin-7-yl]-N-(3-morpholin-4-yl-propyl)-acrylamidecan be made by treating7-fluoro-4-[(3-bromophenyl)amino]pyrido-[4,3-d]pyrimidine withN-(3-aminopropyl)morpholine in dimethylsulfoxide followed by acylationwith acrylic acid and a coupling reagent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDAC) or acryloylchloride and a tertiary base such as diisopropyl ethylamine according tomethods familiar to those skilled in the art. See, for example, WO9519774 A1.

EXAMPLE 2N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-(3-morpholin-4-yl-propyl)-acrylamide

To a stirred solution of4-[(3-bromophenyl)amino]-6-[(3-morpholinopropyl)amino]pyrido[3,4-d]pyrimidine(400 mg, 0.90 mmol), (prepared from4-[(3-bromophenyl)amino]-6-fluoropyrido[3,4-d]pyrimidine and3-morpholinoprop-1-ylamine) DMAP (40 mg) and Et₃N (excess, 2.0 mL) at 0°C. under N₂ was added acryloyl chloride (1.2 mol eq., 1.08 mmol, 89 μL).After 1 hour stirring, a further two portions of acid chloride (89 μLeach) were added over the next 2 hours, and the reaction was thenstirred at 20° C. for 1 hour, diluted with water and extracted withEtOAc. The combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure before beingchromatographed on silica gel eluting with MeOH/EtOAc (1:9) toMeOH/EtOAc (1:5) to giveN-[4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidin-6-yl]-N-[3-morpholinopropyl]acrylamide](142mg, 32%) as a cream powder, mp (CH₂Cl₂/hexane) 178-180° C.

¹H NMR [(CD₃)₂SO]: δ10.15 (s, 1H, NH), 9.15 (s, 1H, aromatic), 8.80 (s,1H, aromatic), 8.47 (s, 1H, aromatic), 8.21 (br s, 1H, H-2′), 7.92 (brd, J=7.6 Hz, 1H, H-6′), 7.41 (t, J=8.0 Hz, 1H, H-5′), 7.37 (dt, J=8.1Hz, J=1.6 Hz, J=1.6 Hz, 1H, H-4′), 6.25 (m, 2H, CH₂CHCO, CH₂CHCO), 5.66(m, 1H, CH₂CHCO), 3.98 (t, J=7.5 Hz, 2H, CH₂NRCO), 3.46 (t, J=4.5 Hz,4H, morpholino methylene), 2.29 (t, J=7.1 Hz, 2H, CH₂CH₂CH₂NRCO), 2.24(br s, 4H, morpholino methylene), 1.73 (quintet, J=7.2 Hz, 2H,CH₂CH₂CH₂).

¹³C NMR: δ164.84, 156.69, 155.80, 151.83, 150.05, 143.01, 140.02,130.51, 129.27, 127.88, 126.76, 124.32, 121.19, 120.82, 113.02, 66.02(×2), 55.05, 53.02 (×2), 45.85, 24.63.

Analysis calculated for C₂₃H₂₅BrN₆O₂.H₂O requires: C, 53.6; H, 5.3; N,16.3%. Found: C, 53.8; H, 5.0; N, 16.3%.

EXAMPLE 3 N-[4-(3-Bromo-phenylamino)-quinazolin-7-yl]acrylamide

To an ice-cold solution of 0.158 g (0.5 mM) of7-amino-4-(3-bromoanilino)-quinazoline [J Med Chem, 1995:3482] and 0.108g of acrylic acid in 5.0 mL of dry dimethylformamide (DMF) was added0.288 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDAC).After stirring for 5 minutes, the mixture became a solution, and the icebath was removed. The reaction continued to stir at room temperature for3 hours. The reaction was then poured into a mixture of ice and waterand made basic with the addition of a saturated solution of sodiumbicarbonate. This aqueous mixture was extracted three times with ethylacetate, and the pooled extracts were dried over magnesium sulfate. Thesolution was filtered and concentrated in vacuo to afford a light yellowsolid. The solid was dissolved in 100 mL of methanol, filtered, andconcentrated in vacuo to approximately 10 mL. The solid whichprecipitated from solution was collected and dried in vacuo at 80° C. togive 50 mg of N-[4-(3-bromo-phenylamino)-quinazolin-7-yl]acrylamide,mp >265° C. Chemical ionization mass spectra: m/e 369.

¹H NMR (D₆-dimethyl sulfoxide): δ5.86 (dd, 1H, J=10.1 , J=1.9), 6.36(dd, 1H, J=17.0, J=1.9), 6.51 (dd, 1H, J=16.9, J=10.1), 7.30 (m, 1H),7.36 (t, 1H, J=8.1), 7.82 (dd, 1H, J=9.2, J=2.2), 7.9 (d, 1H, J=8.0),8.25 (dd, 1H, J=3.6, J=1.9), 8.50 (d, 1H, J=8.9), 8.61 (s, 1H), 9.79 (s,1H, —NH), 10.61 (s, 1H, —NH).

Analysis calculated for C₁₇H₁₃BrN₄O: C, 55.30; H, 3.55; N, 15.17. Found:C, 55.49; H, 3.63; N, 15.26.

EXAMPLE 4N-[4-[(3-Bromophenyl)amino]quinazolin-7-yl]-N-[3-morpholinopropyl]acrylamide

To a solution of 4-[(3-bromophenyl)amino]-7-fluoroquinazoline (0.60 g,1.89 mmol) in Dimethylsulfoxide (DMSO) (10 mL) was added4-(3-aminopropyl)morpholine (7.54 mmol, 1.10 mL). The reaction mixturewas heated at 110° C. for 26 hours and then diluted with water, basifiedby the addition of saturated NaHCO₃ and then extracted with EtOAc. Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, and concentrated in vacuo. Column chromatography on Grade IIIalumina with gradient elution from EtOAc to EtOAc/MeOH (98:2) followedby recrystallization from EtOAc/hexane gave4-[(3-bromophenyl)amino]-7-[(3-morpholinopropyl)amino]-quinazoline (0.65g, 78%) as cream crystals, mp 162-162.5° C.

¹H NMR [(CD₃)₂SO, 200 MHz]: δ9.41 (s, 1H, NH), 8.43 (s, 1H, H-2), 8.24(br s, 1H, H-2′), 8.18 (d, J=9.2 Hz, 1H, H-5), 7.87 (br d, J=8.1 Hz, 1H,H-6′), 7.35-7.18 (m, 2H, H-4′, 5′), 6.88 (dd, J=1.9 Hz, J=9.1 Hz, 1H,H-6′), 6.65 (t, J=5.3 Hz, 1H, CH₂NH), 6.62 (br s, 1H, H-8), 3.60 (t,J=4.6 Hz, 4H, morpholino methylene), 3.19 (dt, J=6.4 Hz, J=6.4 Hz, J=5.8Hz, 1H, CH₂CH₂NH), 2.43-2.33 (m, 6H, morpholino methylene, CH₂CH₂CH₂NH),1.75 (quintet, J=6.8 Hz, 1H, CH₂CH₂CH₂).

¹³C NMR: δ156.56, 154.27, 152.41, 152.32, 141.60, 130.15, 124.90,123.41, 123.31, 121.06, 119.87, 116.51, 105.68, 102.21, 66.13 (×2),55.81, 53.31 (×2), 40.46, 25.14.

To a solution of the above4-[(3-bromophenyl)-amino]-7-[(3-morpholinopropyl)amino]quinazoline (0.10g, 0.230 mmol) in dry DMF (5.0 mL) under N₂ was added acrylic acid(0.565 mmol, 39 μL), Et₃N (100 μL), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl)(0.565 mmol, 108 mg), the reaction mixture was stirred at roomtemperature for 4 days with additional acrylic acid (40 μL),triethylamine Et₃N (100 μL), and EDCI.HCl (100 mg) being added each day.The DMF was then removed in vacuo and the resulting residue diluted withsaturated NaHCO₃ and extracted with EtOAc. The combined organic extractswere washed with brine, dried over anhydrous Na₂SO₄, and concentrated atreduced pressure. Column chromatography on silica gel with gradientelution from MeOH/EtOAc/CH₂Cl₂ (1:4:5) to MeOH/EtOAc/CH₂Cl₂ (2:4:4) gaveat higher R_(f);N-[4-[(3-bromophenyl)amino]quinazolin-7-yl]-N-[3-morpholinopropyl]acrylamide(39 mg, 35%) as a white powder, mp (EtOAc/hexane) 86-88° C. (decomp).

¹H NMR [(CD₃)₂SO, 200 MHz]: δ9.96 (s, 1H, NH), 8.68 (s, 1H, H-2), 8.63(d, J=8.7 Hz, 1H, H-5), 8.23 (br s, 1H, H-2′), 7.91 (dt, J=7.3 Hz, J=2.0Hz, J=2.0 Hz, 1H, H-6′), 7.68-7.58 (m, 2H, aromatic), 7.42-7.31 (m, 2H,aromatic), 6.18 (m, 2H, CH₂CHCO, CH₂CHCO), 5.63 (dd, J=2.0 Hz, J=10.0Hz, 1H, CH₂CHCO), 3.90 (t, J=7.1 Hz, 2H, CH₂CH₂CH₂NCO), 3.51 (t, J=4.3Hz, 4H, morpholino methylene), 2.50 (br s, 2H, CH₂CH₂CH₂NCO), 2.28 (brs, 4H, morpholino methylene), 1.67 (quintet, J=6.5 Hz, 2H, CH₂CH₂CH₂).At lower R_(f); recovered starting material,4-[(3-bromophenyl)amino]-7-[(3-morpholinopropyl)amino]-quinazoline (34%)identical with an authentic sample.

EXAMPLE 5 3-[4-(3-Bromo-phenylamino)-quinazolin-7-ylcarbamoyl]-acrylicacid

To a 50° C. solution of 0.158 g of7-amino-4-(3-bromoanilino)-quinazoline (J Med Chem, 1995:3482) in 10 mLof tetrahydrofuran was added 0.059 g of maleic anhydride. The coldsolution stirred for 15 minutes, and then the ice bath was removed. Thereaction warmed to room temperature where it continued stirring for 15hours. The suspension was heated under reflux for 30 minutes and thenstirred at room temperature another 15 hours. Another 0.059 g of maleicanhydride and 20 mL of tetrahydrofuran were added, and the reaction wasrefluxed for an additional 2 hours. After another 15 hours at roomtemperature, the reaction was refluxed for 15 hours. The reaction wasfiltered, and the light tan solid was recrystallized first fromdimethyl-formamide and then a second time from methanol to afford 0.036g of the desired product.

¹H NMR [(CD₃)₂SO]: δ12.95 (br s, 1H, exchanges with D₂O), 11.04 (br s,1H, exchanges with D₂O), 9.81 (br s, 1H, exchanges with D₂O), 8.62 (s,1H), 8.49 (d, J=9.2 Hz, 1H), 8.24 (s, 1H), 8.17 (d, J=1.7 Hz, 1H), 7.90(d, J=8.4 Hz, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.30(dd, J=1 Hz, 9 Hz, 1H), 6.50 (d, J=12.1 Hz, 1H), 6.37 (d, J=11.8 Hz,1H);

CIMS m/z (relative %): 411.3 (95), 412.3 (23), 413.3 (100), 414.3 (21).

Analysis calculated for C₁₈H₁₃BrN₄O₃: C, 52.32; H, 3.17; N, 13.56.Found: C, 52.57; H, 3.51; N, 13.16.

EXAMPLE 6 3-[4-(3-Bromo-phenylamino)-quinazolin-7-ylcarbamoyl]-acrylicacid ethyl ester

To an ice cold solution of 0.158 g of7-amino-4-(3-bromoanilino)-quinazoline and 0.216 g of monoethyl fumaratein 3 mL of dry dimethylformamide was added 0.288 g of1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl (EDAC).7-Amino-4-(3-bromoanilino)-quinazoline can be made by methods well-knownto those skilled in the art. See, for example, J Med Chem, 1995:3482,which is hereby incorporated by reference. After stirring at 50° C. for5 minutes, the ice bath was removed, and the reaction was permitted towarm to room temperature where it stirred for 15 hours. The reaction waspoured into cold water, and the suspension was made basic with theaddition of a saturated sodium bicarbonate solution. The resulting solidwas collected by filtration, washed with water, and then recrystallizedfrom 50 mL of ethanol to afford 0.052 g of the desired product, mp >260°C.

¹H NMR [(CD₃)₂SO]: δ10.99 (br s, 1H, exchanges with D₂O), 9.82 (br s,1H, exchanges with D₂O), 8.62 (s, 1H), 8.52 (d, J=8.9 Hz, 1H), 8.24 (s,2H), 7.90 (d, J=8.2 Hz, 1H), 7.81 (dd, J=1.7 Hz, 8.9 Hz, 1H), 7.34 (m,2H), 7.26 (d, J=15.7 Hz, 1H), 6.79 (d, J=15.4 Hz, 1H), 3.33 (q, J=7.0Hz, 14.2 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H);

CIMS m/z (relative %): 440 (19%), 441 (100), 442 (37), 443 (78).

Elemental analysis calculated for C₂₀H₁₇BrN₄O₃: C, 54.44; H, 3.88; N,12.70; Br, 18.11. Found: C, 54.32; H, 3.85; N, 12.76; Br, 17.89.

EXAMPLE 7 N-(3-Bromo-phenyl)-quinazolin-4-yl-amine

N-(3-Bromo-phenyl)-quinazolin-4-yl-amine was prepared according tomethods well-known in the art. See, for example, J Med Chem,1995;38(18):3482-3487.

EXAMPLE 8 4-(3-Bromo-phenylamino)-6,7-dimethoxyquinazoline

4-(3-Bromo-phenylamino)-6,7-dimethoxyquinazoline is synthesizedaccording to methods well-known in the art. See, for example, EuropeanPatent Application Number 566 226 A1.

EXAMPLE 9 But-2-enoic acid[4-(3-bromo-phenylamino)-quinazolin-7-yl]-amide

To an ice cold solution of 0.158 g of7-amino-4-(3-bromoanilino)-quinazoline (J Med Chem, 1985:3482) in 5 mLof tetrahydrofuran was added dropwise a solution of 0.105 g of crotonicacid chloride in 5 mL of tetrahydrofuran. When the addition wascomplete, the ice bath was removed and the reaction stirred at roomtemperature for 15 hours. The reaction was filtered to remove the yellowsolid which was washed with tetrahydrofuran and recrystallized from 20mL of boiling methanol to afford 0.060 g of the desired product,mp >250° C.

¹H NMR [(CD₃)₂SO]: δ11.44 (br s, 1H, exchanges with D₂O), 11.04 (s, 1H,exchanges with D₂O), 8.92 (s, 1H), 8.78 (d, J=9.2 Hz, 1H), 8.52 (d,J=1.9 Hz, 1H), 8.05 (t, J=1.8 Hz, 1H), 7.91 (dd, J=2.1 Hz, 9.3 Hz, 1H),7.76 (m, 1H), 7.52 (m, 1H), 7.45 (t, J=8.0 Hz, 1H), 6.70 (m, 1H), 6.28(dd, J=1.7 Hz, 15.1 Hz, 1H), 1.92 (dd, J=1.6 Hz, 6.9 Hz, 3H);

CIMS: 382 (21), 383 (100), 384 (34), 385 (64).

Analysis calculated for C₁₈H₁₅BrN₄O.1 HCl.0.5 H₂O: C, 50.43; H, 4.00; N,13.07; Br, 18.64; Cl, 8.27. Found: C, 50.71; H, 4.00; N, 12.98; Br,18.93; Cl, 7.51.

EXAMPLE 10N-[4-(3-Bromo-phenylamino]-6-(3-morpholin-4-yl-propylamino)-quinazolin-7-yl]-acrylamide

Treatment of 6-chloro-7-nitroquinazolin-4-one (Aust J Chem,1995;48:227-232) with thionyl chloride or POCl₃ affords the4,6-dichloro-7-nitroquinazoline. Reaction with 3-bromoaniline affords amixture of 4-(3-bromophenylamino)-6-chloro-7-nitroquinazoline and4-chloro-6-(3-bromophenylamino)-7-nitroquinazoline which are separatedby column chromatography. Treatment of the desired4-(3-bromophenylamino)-6-chloro-7-nitroquinazoline withN-(3-aminopropyl)-morpholine and subsequent reduction of the nitrofunctionality with, for example, iron in acetic acid affords7-amino-4-(3-bromo-phenylamino)-6-(3-morpholin-4-yl-propylamino)-quinazoline.Acylation to afford the acrylamide is accomplished according to methodof Example 3.

EXAMPLE 11 N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]acrylamide

To a solution of 6-amino-4-[(3-bromophenyl)amino]-quinazoline (2.0 g,6.35 mmol) in dry DMF (20 mL) under N₂ was added acrylic acid (12.7mmol, 0.87 mL). The resulting solution was cooled to 0° C. and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl)(7.62 mmol, 1.46 g) was added. The reaction was stirred at 0° C. for 15minutes and then allowed to warm to room temperature and stirred for afurther 2 hours, after which additional acrylic acid (0.30 mL) andEDCI.HCl (0.30 g) were added. After a further 2 hours, the reaction wascomplete by tlc, solvent was removed under reduced pressure, and theresulting residue diluted with saturated NaHCO₃ and repeatedly extractedwith EtOAc. The combined organic extracts were washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Columnchromatography on grade III alumina eluting with EtOAc/MeOH (95:5)followed by recrystallization from EtOAc/hexane gave a spongy whitesolid, which upon several hours under high vacuum gaveN-[4-[(3-bromophenyl)amino]quinazolin-6-yl]acrylamide (1.06 g, 45%) as acream powder, mp 258-261° C.

¹H NMR [(CD₃)₂SO, 200 MHz]: δ10.51 (s, 1H, CONH), 9.93 (s, 1H, NH), 8.83(br s, 1H, H-5), 8.59 (s, 1H, H-2), 8.18 (br s, 1H, H-2′), 7.94-7.78 (m,3H, H-6′, 8, 5′), 7.40-7.27 (m, 2H, H-7, 4′), 6.54 (dd, J=9.8 Hz, J=17.0Hz, 1H, CH₂CHCO), 6.36 (dd, J=2.1 Hz, J=16.9 Hz, 1H, CH₂CHCO), 5.85 (dd,J=2.0 Hz, J=9.7 Hz, 1H, CH₂CHCO).

Mass spectrum (CI): 371 (95, ⁸¹BrMH⁺), 370 (53, ⁸¹BrM⁺), 369 (100,⁷⁹BrMH⁺), 368 (33, ⁷⁹BrM⁺).

Analysis calculated for C₁₇H₁₃BrN₄O requires: C, 55.30; H, 3.55; N,15.17%. Found: C, 55.19; H, 3.34; N, 14.88%.

EXAMPLE 12 N-[4-(N,N-Dimethylamino)-quinazolin-6-yl]acrylamide

A suspension of 6-nitroquinazolone (3.50 g, 18.5 mmol) in neat SOCl₂ (30mL) containing two drops of DMF was refluxed for 3 hours until it becameclear. The excess SOCl₂ was removed under reduced pressure, and drybenzene was added and then evaporated under reduced pressure to removeall traces of SOCl₂. The resulting crude 4-chloro-6-nitroquinazoline wasdissolved in dry CH₂Cl₂ (50 mL) and washed with saturated Na₂CO₃ (×2),and this solution was then added to a solution of4-amino-2-bromo-N,N-dimethylbenzylamine (20.3 mmol, 4.64 g) in i-PrOH(60 mL) containing Et₃N (excess, 7.0 mL). The resulting reaction mixturewas heated at reflux for 3 hours and then concentrated under reducedpressure, diluted with water, and extracted with EtOAc. The combinedorganic extracts were dried over anhydrous Na₂SO₄, concentrated underreduced pressure, and chromatographed on silica gel eluting withCH₂Cl₂/EtOAc (1:1) to MeOH/CH₂Cl₂/EtOAc (2:9:9) to give4-N,N-dimethylamino-6-nitroquinazoline (2.56 g, 64%), as yellowcrystals, mp (CH₂Cl₂) 131-133° C.

¹H NMR [(CD₃)₂SO], (400 MHz): δ9.02 (d, J=2.4 Hz, 1H, H-5), 8.59 (s, 1H,H-2), 8.47 (dd, J=2.5 Hz, J=9.2 Hz, 1H, H-7), 7.85 (d, J=9.2 Hz, 1H,H-8), 3.46 (s, 6H, N(CH₃)₂).

Further elution gave2-bromo-N,N-dimethyl-4-(6-nitroquinazolin-4-yl)benzylamine (0.62 g, 8%),as a yellow powder, mp (CH₂Cl₂) 198-200° C.

¹H NMR [(CD₃)₂SO], (400 MHz): δ10.47 (br s, 1H, NH), 9.66 (d, J=2.4 Hz,1H, H-5), 8.77 (s, 1H, H-2), 8.57 (dd, J=9.2 Hz, J=2.5 Hz, 1H, H-7),8.21 (d, J=2.0 Hz, 1H, H-2′), 7.95 (d, J=9.1 Hz, 1H, H-8), 7.91 (dd,J=8.4 Hz, 1H, H-6′), 7.49 (d, J=8.5 Hz, 1H, H-5′), 3.46 (s, 2H,CH₂N(CH₃)₂), 2.22 (s, 6H, N(CH₃)₂).

Analysis calculated for C₁₇H₁₆BrN₅O₂1.5H₂O requires: C, 47.6; H, 4.5; N,16.3%. Found: C, 47.7; H, 4.2; N, 15.7%.

To a refluxing solution of the above4-N,N-dimethylamino-6-nitroquinazoline amine (1.20 g, 5.50 mmol) inEtOH/H₂O (2:1, 90 mL) containing glacial acetic acid (4.0 mL) was addedfreshly washed (1N HCl then distilled H₂O) iron powder (4 mol eq., 1.24g) in portions. Identical reaction procedure and workup as above gave,after chromatography on silica gel eluting with CH₂Cl₂/EtOAc (1:1) toMeOH/CH₂Cl₂/EtOAc (1:4:5), 4-N,N-dimethylamino-6-aminoquinazoline (0.87g, 84%), as a pale brown powder, mp (dihydrochloride salt fromMeOH/Et₂O) 258-261° C.

¹H NMR (dihydrochloride salt), [(CD₃)₂SO], (400 MHz): δ14.8 (br s, 1H,NH⁺), 8.65 (s, 1H, H-2), 7.79 (m, 2H, H-5, H-8), 7.57 (dd, J=2.1 Hz,J=8.9 Hz, 1H, H-7), 5.70 (br s, 3H, NH₃ ⁺), 3.55 (s, 6H, N(CH₃)₂).

To a stirred solution containing the above4-N,N-dimethylamino-6-aminoquinazoline (0.65 g, 3.45 mmol), acrylic acid(4 mol eq., 13.8 mmol, 0.95 mL), and pyridine (excess, 1.3 mL) in DMA(20 mL) under N₂ was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI.HCl) (2 mol eq., 6.90 mmol, 1.32 g). The standardprocedure above was followed to give after chromatography on silica geleluting with EtOAc/CH₂Cl₂ (1:1) to MeOH/CH₂Cl₂/EtOAc (1:4:5),[4-(N,N-dimethylamino)quinazolin-6-yl]acrylamide (350 mg, 42%) as acream powder, mp (CH₂Cl₂/hexane) 204-206° C.

¹H NMR [(CD₃)₂SO], (400 MHz): δ10.49 (s, 1H, CONH), 8.80 (d, J=2.2 Hz,1H, H-5), 8.46 (s, 1H, H-2), 7.88 (dd, J=2.4 Hz, J=9.1 Hz, 1H, H-7),7.73 (d, J=9.0 Hz, 1H, H-8), 6.47 (dd, J=17.0 Hz, J=10.1 Hz, 1H,CH₂CHCO), 6.34 (dd, J=17.0 Hz, J=2.0 Hz, 1H, CH₂CHCO), 5.83 (dd, J=10.1Hz, J=2.0 Hz, 1H, CH₂CHCO), 3.32 (s, 6H, N(CH₃)₂).

EXAMPLE 13 N-[4-(3-Methyl-phenylamino)-quinazolin-7-yl]acrylamide

To a stirred solution of 7-amino-4-[(3-methylphenyl)amino]quinazoline(123 mg, 0.49 mmol), acrylic acid (0.04 mL, 0.58 mmol), triethylamine(0.15 mL, 1.1 mmol) in DMF (1.5 mL) at 0° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 mg,0.64 mmol). The resulting light yellow mixture was stirred at 25° C. for20 hours and quenched with water. The solid was collected and purifiedby sonication with a mixture of CH₂Cl₂/EtOAc/MeOH to give the desiredproduct as a yellow solid (75 mg, 49%), mp 269.7-270° C.

¹H NMR [(CD₃)₂SO]: δ10.63 (s, 1H, NH), 9.68 (s, 1H, NH), 8.58 (s, 1H,H2), 8.54 (d, J=9.3 Hz, 1H, H6), 8.25 (d, J=2.2 Hz, 1H, H8), 7.83 (dd,J=9.0, 1.9 Hz, 1H, H5), 7.71 (m, 2H, H2′, H6′), 7.32 (t, J=8.3 Hz, 1H,H5′), 6.99 (d, J=7.1 Hz, 1H, H4′), 6.56 (dd. J=16.8, 10.0 Hz, 1H,CH═CH₂), 6.40 (dd. J=17.1, 5.0 Hz, 1H, CH═CH₂), 5.9 (dd, J=10.3, 2.0 Hz,1H, CH═CH₂), 2.39 (s, 3H, CH₃).

Mass Spectrum (CI): 305 (100, MH⁺), 304 (31.84, M⁺).

Calculated for C₁₈H₁₆N₄O.0.4H₂O: C, 69.39; H, 5.44; N, 17.94%. Found: C,69.19; H, 5.19; N, 17.67%.

EXAMPLE 14 N-[4-(3-Chloro-phenylamino)-quinazolin-7-yl]acrylamide

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5mmol) was added to a solution of6-amino-4[(3-chlorophenyl)amino]quinazoline (136 mg, 0.5 mmol) andacrylic acid (108 mg, 1.5 mmol) in dimethylformamide (DMF) (5 mL),stirred under nitrogen at 0° C. After 15 minutes the reaction mixturewas stirred at 25° C. for 18 hours, and then poured onto ice-water (50mL) and after 1 hour the precipitate was collected by Buchnerfiltration. The residue was rinsed, air dried, dissolved in the minimumof 25° C. methanol (MeOH) (60 mL), concentrated at 25° C. under reducedpressure to below 10 mL, and recrystallized at 0° C. to giveN-[4-[(3-chlorophenyl)-amino]quinazolin-7-yl]acrylamide (33 mg, 20%) asa light orange solid, mp 296.5-298.5° C.

Calculated for C₁₇H₁₃ClN₄O.0.08 CH₃OH.0.25 H₂O: C, 61.82; H, 4.20; N,116.89%. Found: C, 61.92, H, 4.23; N, 116.72%.

¹H NMR [(CD₃)₂SO): δ10.61 (brs, 1H, NH), 9.80 (s, 1H, NH), 8.62 (s, 1H,H2), 8.50 (d, J=9.0 Hz, H5), 8.25 (d, J=2.0 Hz, 1H, H8), 8.13 (t, J=2.0Hz, 1H, H2′), 7.87-7.78 (m, 2H, H6 & H6′), 7.42 (t, J=8.2 Hz, 1H, H5′),7.16 (dd, J=2.2, 7.9 Hz, 1H, H4′), 6.51 (dd, J=10.0, 17.1 Hz, 1H,CH═CH₂), 6.35 (dd, J=1.8, 17.1 Hz, 1H, CH═CH₂), 5.86 (dd, J=1.8, 10.1Hz, 1H, CH═CH₂).

Mass Spectrum (CI) 327 (32, ³⁷ClMH⁺), 326 (25, ³⁷ClM⁺, ¹³C ³⁵ClMH⁺), 325(100, ³⁵ClMH⁺), 322 (22, ³⁵ClMH⁺).

EXAMPLE 15 N-[4-(3-Bromo-phenylamino)-quinazolin-7-yl]-methacrylamide

To a stirred solution of 7-amino-4-[(3-bromo-phenyl)amino]quinazoline (JMed Chem, 1995;38:3482) (150 mg, 0.48 mmol) in dry DMF (20 mL) was addedmethacrylic acid (200 mg) and1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl)(2.5 mol, 228 mg), the reaction mixture was stirred overnight thenfurther amounts of EDCI.HCl (230 mg) and methacrylic acid (200 mg) wereadded. After a further 2 days stirring the solvent was removed undervacuum and the residue diluted with saturated NaHCO₃, extracted withethyl acetate (EtOAc) and then the combined organic extracts were driedover anhydrous Na₂SO₄, concentrated under reduced pressure andchromatographed on silica gel eluting with MeOH/CH₂Cl₂/EtOAc (5:45:50)to MeOH/CH₂Cl₂/EtOAc (10:40:50) to giveN-[4-[(3-bromophenyl)amino]-quinazolin-7-yl]-2-methyl-acrylamide (43 mg,24%) as a pale brown solid, mp (CH₂Cl₂/hexane) 255-259° C.

¹H NMR [(CD₃)₂SO], (400 MHz) δ10.22 (s, 1H, CONH), 9.76 (s, 1H, NH),8.61 (s, 1H, H-2), 8.48 (d, J=9.2 Hz, 1H, H-5), 8.26 (m, 2H, H-2′, 8),7.92 (m, 2H, H-6′, 6), 7.36 (t, J=8.0 Hz, 1H, H-5′), 7.30 (br d, J=8.3Hz, 1H, H-4′), 5.92 (s, 1H, CH₂C(CH₃)CO), 5.63 (s, 1H, CH₂C(CH₃)CO),2.00 (s, 3H, CH₂C(CH₃)CO).

Analysis calculated for C₁₈H₁₅BrN₄O requires: C, 56.4; H, 4.0; N, 14.6%.Found: C, 56.1; H, 4.0; N, 14.1%.

EXAMPLE 16N-[4-(3-Bromo-phenylamino)-quinazolin-7-yl]ethenyl-sulfonamide

A solution of 7-amino-4-[(3-bromophenyl)-amino]quinazoline (J Med Chem,1995;38:3482) (500 mg, 1.59 mmol), triethylamine (Et₃N) (0.60 mL) anddimethylamine pyridine (DMAP) (catalytic) in tetrahydrofuran (THF) (30mL) was reacted with chloroethanesulfonyl chloride (1.6 mol eq., 2.54mmol, 265 μL) at 25° C. for 1 hour, stirred under N₂. The reactionmixture was diluted with saturated NaHCO₃ and extracted with EtOAc. Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, concentrated under reduced pressure, and chromatographed onsilica gel eluting with MeOH/CH₂Cl₂/EtOAc (3:47:50). Crystallizationfrom CH₂Cl₂/hexane, gaveN-[4-[(3-bromophenyl)amino]-quinazolin-7-yl]vinylsulfonamide (80 mg,12%) as a cream powder, mp 218° C. decomposes (dec).

¹H NMR [(CD₃)₂SO], (400 MHz) δ10.73 (s, 1H, SO₂NH), 9.80 (s, 1H, NH),8.59 (s, 1H, H-2), 8.47 (d, J=9.1 Hz, 1H, H-5), 8.21 (br s, 1H, H-2′),7.87 (br d, J=8.0 Hz, 1H, H-6′), 7.47 (d, J=2.1 Hz, 1H, H-8), 7.40 (dd,J=9.0 Hz, J=2.2 Hz, 1H, H-6), 7.36 (t, J=8.0 Hz, 1H, H-5′), 7.30 (br d,J=8.0 Hz, 1H, H-4′), 6.93 (dd, J=16.4 Hz, J=9.9 Hz, 1H, CH₂CHSO₂), 6.28(d, J=16.4 Hz, 1H, CH₂CHSO₂), 6.15 (d, J=9.9 Hz, 1H, CH₂CHSO₂).

Analysis calculated for C₁₆H₁₃BrN₄O₂S requires: C, 47.4; H, 3.2%. Found:C, 47.3; H, 3.5%.

EXAMPLE 17 N-[4-(3-Bromo-phenylamino)-quinazolin-7-yl]propanamide

To a solution of 7-amino-4-[(3-bromophenyl)amino]-quinazoline (163 mg,0.52 mmol) in dry THF (3 mL) stirred under N₂ at 25° C. was addeddropwise propionyl chloride (0.05 mL, 0.58 mmol). A yellow solid formedat once. After 1 hour the solid was collected by Buchner filtration andwashed with ether then dried. Recrystallized from wet methanol affordedthe desired product as bright yellow solid (81 mg, 38%), mp 282-283° C.

¹H NMR [(CD₃)₂SO]: δ11.4 (brs, 1H, NH), 10.76(s, 1H, NH), 8.90 (s, 1H,H8), 8.64 (d, J=9.0 Hz, 1H, H6), 8.42 (s, 1H, H2), 8.06 (s, 1H, H2′),7.80(dd, J=9.2, 1.9 Hz, 1H, H5), 7.74 (d, J=7.8 Hz, 1H, H4′), 7.50 (d,J=8.0 Hz, 1H, H6′), 7.45 (t, J=8.0 Hz, 1H, H5′), 2.48 (q, J=7.6 Hz, 2H,CH₂), 1.13 (t, J=7.5 Hz, 3H, CH₃).

Mass Spectrum (APCI): 373 (100, ⁸¹BrMH⁺), 372 (21, ⁸¹BrM⁺), 371 (96,⁷⁹BrMH⁺).

Calculated for C₁₇H₁₅N₄BrO.HCl.0.2H₂O: C, 49.64; H, 4.02; N, 13.63%Found: C, 49.48; H, 3.91; N, 13.57%.

EXAMPLE 18 N-[4-[(3-Chlorophenyl)amino]quinazolin-6-yl]acrylamide

1-3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1902 mg, 1mmol) was added to a solution of6-amino-4[(3-chlorophenyl)amino]quinazoline (136 mg, 0.5 mmol) acrylicacid (74 mg, 1.0 mmol) and pyridine (201 mg, 2.5 mmol) in THF/DMF (4:1,2.5 mL), stirred under nitrogen at 0° C. After 20 minutes the reactionmixture was stirred at 25° C. for 3 hours, and then poured onto water(12.5 mL), and extracted with EtOAc (2×10 mL). The combined extractswere treated with dilute hydrochloric acid (0.5 M, 10 mL), and theprecipitate was collected by Buchner filtration, rinsed with water (10mL), ether (2×10 mL), and air dried to giveN-[4-[(3-chlorophenyl)amino]quinazolin-6-yl]acrylamide hydrochloride (93mg, 48%) as a dull yellow solid, mp 223-227° C.

Calculated for C₁₈H₁₃ClN₄O.HCl.1.5 H₂O: C,52.59; H, 4.41;N, 14.43%.Found: C, 52.43, H, 4.37; N, 14.27%.

¹H NMR[(CD₃)₂SO]: δ11.46 (brs, 1H, NH), 11.05 (s, 1H, NH), 9.13 (d,J=2.0 Hz, 1H, H5), 8.90 (s, 1H, H2), 8.12 (dd, J=2.0, 9.0 Hz, 1H, H7),7.99 (d, J=9.0 Hz, 1H, H8), 7.88 (t, J=2.0 Hz, 1H, H2′), 7.68 (dd,J=6.1, 1.0 Hz, 1H, H6′), 7.51 (t, J=8.0 Hz, 1H, H5′), 7.37 (dd, J=8.1,1.2 Hz, 1H, H-4′), 6.63 (dd, J=10.3, 17.1 Hz, 1H, CH═CH₂), 6.37 (dd,J=1.6, 17.1 Hz, 1H, CH═CH₂), 5.87 (dd, J=1.7, 10. Hz, 1H, CH═CH₂).

Mass Spectrum, Chemical Ionization (CI): 327 (8, ³⁷ClMH⁺), 325 (37,³⁵ClMH⁺), 135 (100).

EXAMPLE 19 N-[4-[(3-methylphenyl)amino]quinazolin-6-yl]acrylamide

Isobutyl chloroformate (20.35 g, 0.15 mol) was added dropwise over 20minutes to a solution of acrylic acid (10.82 g), 0.15 mol) andtriethylamine (30.19 g, 0.30 mol) in THF (400 mL), stirred undernitrogen at 0° C. The slurry was stirred at that temperature for 30minutes, and then 6-amino-4[(3-methylphenyl)amino]-quinazoline (27.71 g,107 mmol) in DMF (80 mL) was added dropwise over 45 minutes. After afurther 4 hours, further mixed anhydride (from acrylic acid (3.61 g, 50mmol), isobutyl chloroformate (6.80 g, 50 mmol) and triethylamine (10.1g, 100 mmol) in THF (100 mL) at 0° C.) was added in one portion. After afurther 15 minutes, the reaction mixture was stirred at 25° C. for 30minutes, and then poured onto ice-water (1 L). Ether (200 mL) was addedand the phases were separated. The aqueous phase was extracted withEtOAc (500 mL), and the combined organic phases were washed with water(500 mL), and saturated brine (250 mL). The solution was stirred withanhydrous MgSO₄ for 2 minutes, filtered, and silica gel (150 g) wasadded. The mixture was stripped to dryness, and used as the origin of aflash silica chromatography column (700 g), eluting withacetone/dichloromethane (25% 4 L, 35% 8 L, 40% 4 L). The solvent wasstripped from the appropriate fractions and the residue was suspended inEtOAc (200 mL) refluxed for 5 minutes and sonicated at 60° C. for 20minutes, then collected by Buchner filtration, rinsed with EtOAc (3×25mL), and dried in a vacuum oven at 75° C. for 16 hours, to giveN-[4-[(3-methyl-phenyl)amino]quinazolin-6-yl)acrylamide (11.38 g, 35%)as a light yellow solid, mp 247-8° C.

Calculated for C₁₈H₁₆N₄O.0.1 H₂O: C, 70.61; H, 5.33; N, 18.30%. Found:C, 70.33; H, 5.19; N, 18.17%.

¹H NMR [(CD₃)₂SO]: δ10.49 (brs, 1H, NH), 9.76 (brs, 1H, NH), 8.75 (d,J=2.5 Hz, 1H, H5), 8.52 (s, 1H, H2), 7.89 (dd, J=2.0, 9.2 Hz, 1H, H7),7.77 (d, J=8.9 Hz, 1H, H8), 7.64-7.60 (m, 2H, H6′ & H2′), 7.26 (dt,J_(d)=1.4 Hz, J_(t)=7.5 Hz, 1H, H5′), 6.94 (d, J=7.2 Hz, 1H, H4′), 6.53(dd, J=10.1, 16.9 Hz, 1H, CH═CH₂), 6.34 (dd, J=1.9, 16.9 Hz, 1H,CH═CH₂), 5.84 (dd, J=1.9, 10.1 Hz, 1H, CH═CH₂) 2.34 (s, 3H, Me).

Mass Spectrum (CI) 305 (100, MH⁺), 304 (49, M⁺).

EXAMPLE 20N-[4-[(3-(Trifluoromethyl)phenyl)amino]quinazolin-6-yl]acrylamide

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg, 1.1mmol) was added to a solution of6-amino-4[(3-(trifluoromethyl)phenyl)-amino]quinazoline (153 mg, 0.5mmol) acrylic acid (73 mg, 1.0 mmol) and pyridine (206 mg, 2.5 mmol) inTHF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 15 minutesthe reaction mixture was stirred at 25° C. for 1 hour, and then recooledto 0° C. Dilute hydrochloric acid (0.5 M, 10 mL) was added, and after 15minutes the precipitate was collected by Buchner filtration. The residuewas rinsed with water (5 mL) and ether (2×5 mL) and dried in a vacuumoven at 75° C. overnight to giveN-[4-[(3-(trifluoromethyl)phenyl)amino]quinazolin-6-yl]acrylamidehydrochloride (87 mg, 45%) as a light greenish solid, mp 195-199° C.

Calculated for C₁₈H₁₃F₃N₄O.HCl.0.5 H₂O: C, 53.54; H, 3.74;N, 13.88%.Found: C, 53.70; H, 3.72; N, 13.73%.

¹H NMR [(CD₃)₂SO]: δ11.59 (brs, 1H, NH), 10.99 (s, 1H, NH), 9.17 (d,J=2.0 Hz, H5), 8.92 (s, 1H, H2), 8.12 (s, 1H, H2′), 8.10 (dd, J=2.0, 9.2Hz, 1H, H7), 8.04 (d, J=8.0 Hz, 1H, H6′), 7.98 (d, J=9.0 Hz, 1H, H8),7.74 (t, J=7.9 Hz, 1H, H5′), 7.68 (d, J=7.8 Hz, 1H, H4′), 6.60 (dd,J=10.1, 16.9 Hz, 1H, CH═CH₂), 6.38 (dd, J=1.6, 16.9 Hz, 1H, CH═CH₂),5.89 (dd, J=1.6, 10.1 Hz, 1H, CH═CH₂).

Mass Spectrum (CI) 359 (45, MH⁺), 134 (100).

EXAMPLE 21N-[4-[(3-Bromophenyl)amino]-7-[3-(4-morpholino)propoxy]qiuinazolin-6-yl]acrylamide

Sodium metal (27.6 mmol, 0.63 g) was added to a solution of3-morpholinopropan-1-ol (22.0 mmol, 3.20 g) in THF (60 mL) under N₂. Theresulting suspension was stirred at 20° C. for 2 hours and thencannulated into a solution of4-[(3-bromophenyl)amino]-7-fluoro-6-nitro-quinazoline, J Med Chem, 1996(39):918) (2.0 g, 5.51 mmol) in THF (50 mL) under N₂. The solution wasthen heated at reflux for 24 hours before being diluted with water andextracted with EtOAc. The combined organic extracts were dried overanhydrous Na₂SO₄, concentrated under reduced pressure andchromatographed on alumina eluting with EtOAc/hexane (1:1) toMeOH/CH₂Cl₂/EtOAc (2:3:5) to give4-[(3-bromophenyl)amino]-7-[(3-morpholino)propyloxy]-6-nitroquinazoline(1.75 g, 65%) as a yellow powder, mp (MeOH) 216-220° C.

¹H NMR [(CD₃)₂SO]: δ10.12 (s, 1H, NH), 9.24 (s, 1H, aromatic), 8.69 (s,1H, aromatic), 8.19 (t, J=1.8 Hz, 1H, H-2′), 7.88 (dt, J_(d)=7.8 Hz,J_(t)=1.4 Hz, 1H, H-6′), 7.49 (s, 1H, aromatic), 7.38 (t, J=8.0 Hz, 1H,H-5′), 7.34 (dt, J_(d)=8.1 Hz, J_(t)=1.4 Hz, 1H, H-4′), 4.35 (t, J=6.2Hz, 2H, CH₂CH₂CH₂O), 3.58 (t, J=4.6 Hz, 4H, morpholino methylene), 2.45(t, J=7.0 Hz, 2H, NCH₂CH₂CH₂), 2.37 (br s, 4H, morpholino methylene),1.94 (quintet, J=6.6 Hz, 2H, CH₂CH₂CH₂).

¹³C NMR: δ157.76, 157.26, 153.76, 153.21, 140.32, 138.86, 130.37,126.38, 124.26, 121.70, 121.13, 120.72, 110.11, 107.88, 67.87, 66.13(×2), 54.42, 53.28 (×2), 25.30.

Analysis calculated for C₂₁H₂₂BrN₅O.4.0.75 H₂O requires: C, 50.3; H,4.7; N, 14.0%. Found: C, 50.3; H, 4.4; N, 13.8%.

Freshly washed (1N HCl then distilled H₂O) iron powder (12 mmol, 0.686g) was added in portions to a refluxing solution of the abovenitroquinazoline (1.50 g, 3.07 mmol) in EtOH/H₂O (2:1, 80 mL) containingglacial acetic acid (2.0 mL). The resulting suspension was heated atreflux with vigorous stirring for 20 minutes then cooled, basified bythe addition of concentrated NH₃ and filtered through a pad of celite.The celite pad was washed with EtOH before the filtrate was concentratedunder reduced pressure, diluted with water, and extracted with EtOAc.The combined organic extracts were dried over anhydrous Na₂SO₄,concentrated under reduced pressure, and chromatographed on Grade IIIalumina eluting with CH₂Cl₂/EtOAc (1:1) to MeOH/EtOAc (2:98) to give6-amino-4-[(3-bromophenyl)-amino]-7-[(3-morpholino)propyloxy]quinazoline(1.08 g, 77%) as a pale brown powder, mp (EtOAc/hexane) 158-160° C.

¹H NMR [(CD₃)₂SO], (400 MHz): δ9.37 (s, 1H, NH), 8.40 (s, 1H, aromatic),8.24 (t, J=1.9 Hz, 1H, H-2′), 7.86 (ddd, J=8.2, 0.8, 1.8 Hz, 1H, H-6′),7.42 (s, 1H, aromatic), 7.30 (t, J=8.1 Hz, 1H, H-5′), 7.21 (ddd, J=8.2,1.0, 1.9 Hz, 1H, H-4′), 7.09 (s, 1H, aromatic), 5.36 (s, 2H, NH₂), 4.20(t, J=6.2 Hz, 2H, CH₂CH₂CH₂O), 3.59 (t, J=4.6 Hz, 4H, morpholinomethylene), 2.50 (t, J=7.3 Hz, 2H, NCH₂CH₂CH₂), 2.39 (br s, 4H,morpholino methylene), 1.99 (quintet, J=6.7 Hz, 2H, CH₂CH₂CH₂).

¹³C NMR: δ154.88, 151.94, 150.19, 144.84, 141.94, 138.50, 130.16,124.66, 123.02, 121.09, 119.65, 110.42, 106.37, 100.81, 66.45, 66.14(×2), 54.77, 53.29 (×2), 25.50.

Analysis calculated for C₂₁H₂₄BrN₅O₂.0.25 H₂O requires: C, 54.5; H, 5.3;N, 15.1%. Found: C, 54.6; H, 5.5; N, 15.0%.

To a stirred solution of the above 6-amino-quinazoline (0.50 g, 1.09mmol), acrylic acid (6 mol, 6.54 mmol, 449 μL), and Et₃N (excess, 2.0mL) in DMF (20 mL) under N₂ was added1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl)(3 mol, 3.27 mmol, 627 mg). The reaction was stirred at 0° C. for 15minutes and then allowed to warm to room temperature and stirred for afurther 2 hours. The solvent was removed under reduced pressure, and theresulting residue was diluted with saturated NaHCO₃ and repeatedlyextracted with EtOAc. The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. Chromatography on Grade III alumina eluting with EtOAc/hexane(9:1) to MeOH/EtOAc (2:98),N-[4-[(3-bromophenyl)amino]-7-[(3-morpholino)propyloxy]-quinazolin-6-yl]acrylamide(329 mg, 59%) as a cream powder, mp (EtOAc/Et₂O/hexane) 170-172° C.

¹H NMR [(CD₃)₂SO]: δ9.78 (s, 1H, CONH), 9.62 (s, 1H, NH), 8.89 (s, 1H,aromatic), 8.56 (s, 1H, aromatic), 8.18 (t, J=1.9 Hz, 1H, H-2′), 7.88(br d, J=8.2 Hz, 1H, H-6′), 7.34 (t, J=8.1 Hz, 1H, H-5′), 7.30 (s, 1H,aromatic), 7.27 (ddd, J=7.9, 1.4, 0.8 Hz, 1H, H-4′), 6.72 (dd, J=17.0,10.2 Hz, 1H, CH₂CHCO), 6.33 (dd, J=17.0, 1.9 Hz, 1H, CH₂CHCO), 5.83 (dd,J=10.2, 1.9 Hz, 1H, CH₂CHCO), 4.27 (t, J=6.3 Hz, 2H, CH₂CH₂CH₂O), 3.58(t, J=4.6 Hz, 4H, morpholino methylene), 2.48 (t, J=7.1 Hz, 2H,NCH₂CH₂CH₂), 2.38 (br s, 4H, morpholino methylene), 1.99 (quintet, J=6.7Hz, 2H, CH₂CH₂CH₂).

¹³C NMR: δ163.49, 156.68, 154.96, 153.92, 149.19, 141.20, 131.58,130.19, 127.16, 126.95, 125.52, 123.97, 121.03, 120.52, 116.78, 108.80,107.28, 66.96, 66.14 (×2), 54.54, 53.28 (×2), 25.31.

Analysis calculated for C₂₄H₂₆BrN₅O₃.0.5 H₂O requires: C, 55.3; H, 5.2;N, 13.4%. Found: C, 55.3; H, 4.9; N, 13.3%.

EXAMPLE 22N-[4-[(3-Methylphenyl)amino)-7-[3-(4-morpholino)-propoxy]quinazolin-6-yl]acrylamide

A suspension of 7-fluoro-6-nitroquinazolone (2.40 g, 11.48 mmol) in neatSOCl₂ (25 mL) containing 2 drops of DMF was refluxed for 3 hours untilit became clear. The excess SOCl₂ was then removed in vacuo and drybenzene was added to the residue and then distilled under reducedpressure to remove all traces of SOCl₂ giving crude4-chloro-7-fluoro-6-nitroquinazoline, which was dissolved in dry CH₂Cl₂(50 mL) and added to a stirred solution of m-toluidine in isopropanol(i-PrOH) (30 mL). The reaction mixture was stirred at 20° C. for 30minutes and then hexane (200 mL) was added to precipitate the product asthe HCl salt. The precipitate was filtered, washed with hexane, and thendissolved in MeOH/H₂O (4:1, 150 mL) with gentle warming. Excess Et₃N wasthen added to the solution followed by water (400 mL) to precipitate theproduct as the free base which was then filtered, washed with water anddried under reduced pressure to give7-fluoro-4-[(3-methylphenyl)-amino]-6-nitroquinazoline (3.01 g, 88%) asa yellow powder, mp (CH₂Cl₂/hexane) 191-192° C.

¹H NMR [(CD₃)₂SO]: δ10.38 (s, 1H, NH), 9.62 (d, J=8.1 Hz, 1H, H-5), 8.67(s, 1H, H-2), 7.80 (d, J=12.6 Hz, 1H, H-8), 7.63 (br d, J=8.2 Hz, 1H,H-6′), 7.60 (br s, 1H, H-2′), 7.31 (t, J=7.8 Hz, 1H, H-5′), 7.03 (br d,J=7.5 Hz, 1H, H-4′), 2.35 (s, 3H, ArCH₃).

Analysis calculated for C₁₅H₁₁FN₄O₂ requires: C, 60.4; H, 3.7; N, 18.8%.Found: C, 60.6; H, 3.6; N, 19.0%.

To a solution of 3-morpholinopropan-1-ol (8.40 mmol, 1.22 g) in THF (40mL) under N₂ was added sodium metal (11.8 mmol, 0.27 g). The resultingsuspension was stirred at 20° C. for 2 hours and then cannulated into asolution of 7-fluoro-4-[(3-methyl-phenyl)amino]-6-nitroquinazoline (0.70g, 2.35 mmol) in THF (30 mL) under N₂. The reaction procedure and workupabove were followed to give after chromatography on silica gel elutingwith MeOH/CH₂Cl₂/EtOAc (5:45:50) to MeOH/CH₂C0.50/EtOAc (3:7:10)4-[(3-methylphenyl)-amino]-7-[(3-morpholino)propyloxy]-6-nitroquinazoline(0.87 g, 88%) as a yellow powder, mp (CH₂Cl₂/hexane) 169-170° C.

¹H NMR [(CD₃)₂SO]: δ10.00 (s, 1H, NH), 9.26 (s, 1H, aromatic), 8.62 (s,1H, aromatic), 7.64 (br d, J=8.1 Hz, 1H, H-6′), 7.62 (br s, 1H, H-2′),7.45 (s, 1H, aromatic), 7.29 (t, J=7.8 Hz, 1H, H-5′), 6.99 (br d, J=7.5Hz, 1H, H-4′), 4.34 (t, J=6.1 Hz, 2H, CH₂CH₂CH₂O), 3.58 (t, J=4.6 Hz,4H, morpholino methylene), 2.46 (t, J=7.0 Hz, 2H, NCH₂CH₂CH₂), 2.38 (brs, 4H, morpholino methylene), 2.35 (s, 3H, CH₃Ar), 1.94 (quintet, J=6.6Hz, 2H, CH₂CH₂CH₂).

Analysis calculated for C₂₂H₂₅N₅O₄ requires: C, 62.4; H, 6.0; N, 16.5%.Found: C, 62.2; H, 6.1; N, 16.5%.

A solution of the above nitroquinazoline (0.71 g, 1.68 mmol) inMeOH/EtOAc (2:1, 60 mL) was hydrogenated (60 psi) over Pd—C for 6 hoursand then filtered through celite. The filtrate was then concentratedunder reduced pressure to give6-amino-4-[(3-methyl-phenyl)amino]-7-[(3-morpholino)propyloxy]quinazolinewhich was used without further characterization. To a stirred solutionof this (0.7 g, 1.8 mmol), acrylic acid (6 mol, 10.8 mmol, 776 μL), andEt₃N (excess, 4.0 mL) in DMF (20 mL) under N₂ was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl)(3 mol, 5.38 mmol, 1.03 g). The standard procedure above was followed togive after chromatography on silica gel eluting with CH₂Cl₂/EtOAc (1:1)to MeOH/CH₂Cl₂/EtOAc (3:7:10),N-[4-[(3-methyl-phenyl)amino]-7-[(3-morpholino)propyloxy]quinazolin-6-yl]acrylamide(175 mg, 22%) as a cream powder, mp (EtOAc/Et₂O) 69-72° C.

¹H NMR [(CD₃)₂SO], (400 MHz): δ9.60 (s, 1H, exchangeable), 9.59 (s, 1H,NH), 8.86 (s, 1H, H5), 8.48 (s, 1H, H2), 7.62 (br d, J=8.0 Hz, 1H,H-6′), 7.61 (br s, 1H, H-2′), 7.26 (s, 1H, H8), 7.25 (t, J=7.8 Hz, 1H,H-5′), 6.92 (br d, J=7.4 Hz, 1H, H-4′), 6.70 (dd, J=16.9, 10.2 Hz, 1H,CH₂CHCO), 6.32 (dd, J=16.9, 1.9 Hz, 1H, CH₂CHCO), 5.82 (dd, J=10.2, 1.9Hz, 1H, CH₂CHCO), 4.26 (t, J=6.3 Hz, 2H, CH₂CH₂CH₂O), 3.58 (t, J=4.6 Hz,4H, morpholino methylene), 2.48 (t, J=7.1 Hz, 2H, NCH₂CH₂CH₂), 2.38 (brs, 4H, morpholino methylene), 2.33 (s, 3H, CH₃Ar), 1.99 (quintet, J=6.7Hz, 2H, CH₂CH₂CH₂).

Analysis calculated for C₂₅H₂₉N₅O₃.0.25 H₂O requires: C, 66.4; H, 6.6;N, 15.5%. Found: C, 66.3; H, 6.9; N, 15.9%.

EXAMPLE 23N-[4-[(3-Methylphenyl)amino]-7-[3-(4,N-methyl-1,N-piperazino)propoxyl]quinazolin-6-yl]acrylamide

Sodium metal (10.1 mmol, 0.23 g) was added to a solution of3-N-(4-methylpiperazinyl)propan-1-ol (6.71 mmol, 1.06 g) in THF (15 mL)under N₂. The resulting suspension was stirred at 20° C. for 2 hours andthen cannulated into a solution of7-fluoro-4-[(3-methylphenyl)amino]-6-nitroquinazoline (0.50 g, 1.68mmol) in THF (20 mL) under N₂. The dark red solution was then heated atreflux for 24 hours before being diluted with water and extracted withEtOAc. The combined organic extracts were dried over anhydrous Na₂SO₄,concentrated under reduced pressure and chromatographed on aluminaeluting with EtOAc/hexane (1:1) to EtOAc (2:3:5), to give4-[(3-methylphenyl)-amino]-7-[3-N-(4-methylpiperazinyl)propyloxy]-6-nitro-quinazoline(0.67 g, 91%) as a yellow powder, mp (Et₂O/hexane) 155-156° C.

¹H NMR [(CD₃)₂SO]: δ10.00 (s, 1H, NH), 9.26 (s, 1H, H5, H2H5), 8.61 (s,1H, H2), 7.64 (br d, J=8.4 Hz, 1H, H-6′), 7.62 (br s, 1H, H-2′), 7.43(s, 1H, H8), 7.29 (t, J=7.8 Hz, 1H, H-5′), 6.99 (br d, J=7.4 Hz, 1H,H-4′), 4.32 (t, J=6.0 Hz, 2H, CH₂CH₂CH₂O), 2.44 (t, J=7.0 Hz, 2H,NCH₂CH₂CH₂), 2.39-2.28 (br s, 8H, piperazinyl methylene), 2.34 (s, 3H,CH₃Ar), 2.14 (s, 3H, CH₃N), 1.92 (quintet, J=6.6 Hz, 2H, CH₂CH₂CH₂).

Analysis calculated for CH₂₈N₆O₃ requires: C, 63.3; H, 6.5; N, 19.3%.Found: C, 63.4; H, 6.8; N, 19.6%.

A solution of the above nitroquinazoline (0.61 g, 1.40 mmol) inMeOH/EtOAc (2:1, 50 mL) was hydrogenated (60 psi) over Pd—C for 5 hoursand then filtered through celite. The filtrate was then concentratedunder reduced pressure and chromatographed on Grade III alumina elutingwith MeOH/EtOAc (5:95) to give6-amino-4-[(3-methylphenyl)amino]-7-[3-N-(4-methylpiperazinyl)propyloxy]quinazoline(361 mg) which appeared to rapidly discolor and was used without furthercharacterization. To a stirred solution of this (0.36 g, 0.89 mmol),acrylic acid (6 mol, 5.53 mmol, 366 μL), and Et₃N (excess, 2.0 mL) inDMF (20 mL) under N₂ was added1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI.HCl)(3 mol, 2.66 mmol, 511 mg). The standard procedure above was followed togive, after chromatography on Grade III alumina eluting with EtOAc toMeOH/EtOAc (2:98),N-[4-[(3-methylphenyl)amino]-7-[3-N-(4-methylpiperazinyl)-propyloxy]quinazolin-6-yl]acrylamide(65 mg, 16%) as a colorless glass, mp (Et₂O/hexane) 60-66° C.

¹H NMR [(CD₃)₂SO]: δ9.60 (s, 1H, NH), 9.59 (s, 1H, NH), 8.86 (s, 1H,H5), 8.48 (s, 1H, H2), 7.62 (br d, J=8.0 Hz, 1H, H-6′), 7.62 (br s, 1H,H-2′), 7.25 (t, J=8.1 Hz, 1H, H-5′), 7.25 (s, 1H, H8), 6.92 (br d, J=7.5Hz, 1H, H-4′), 6.70 (dd, J=17.0 Hz, J=10.2 Hz, 1H, CH₂CHCO), 6.31 (dd,J=16.9, 1.8 Hz, 1H, CH₂CHCO), 5.83 (dd, J=10.2, 1.8 Hz, 1H, CH₂CHCO),4.24 (t, J=6.3 Hz, 2H, CH₂CH₂CH₂O), 2.47 (t, J=7.1 Hz, 2H, NCH₂CH₂CH₂),2.41-2.28 (br s, 8H, piperazinyl methylene), 2.33 (s, 3H, CH₃Ar), 2.15(s, 3H, CH₃N), 1.97 (quintet, J=6.8 Hz, 2H, CH₂CH₂CH₂). EI HRMS (M⁺)C₂₆H₃₂N₆O₂ requires 460.2587. Found: 460.2576.

EXAMPLE 24N-]4-[(3-Bromophenyl)amino]-7-]3-(4,N-methyl-1,N-piperazino)propoxyl]quinazolin-6-yl]acrylamide

To a solution of 3-N-(4-methylpiperazinyl)propan-1-ol (8.81 mmol, 1.39g) in THF (40 mL) under N₂ was added sodium metal (13.2 mmol, 0.30 g).The resulting suspension was stirred at 20° C. for 2 hours and thencannulated into a solution of4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline [J Med Chem,1996(39):918] (0.80 g, 2.20 mmol) in THF (30 mL) under N₂. Identicalreaction procedure and workup as in the previous example gave, afterchromatography on silica gel eluting with MeOH/CH₂Cl₂/EtOAc (1:9:10) toMeOH/CH₂Cl₂./EtOAc (2:3:5),4-[(3-bromophenyl)amino]-7-[3-N-(4-methylpiperazinyl)propyloxy]-6-nitroquinazoline(0.36 g, 33%) as a yellow powder, mp (trihydrochloride salt) (MeOH/Et₂O)233° C. (dec).

¹H NMR (free base, (CD₃)₂SO]: δ10.12 (s, 1H, NH), 9.24 (s, 1H, H5), 8.69(s, 1H, H2), 8.19 (br s, 1H, H-2′), 7.88 (br d, J=7.8 Hz, 1H, H-6′),7.47 (s, 1H, H8), 7.38 (t, J=7.8 Hz, 1H, H-5′), 7.34 (dt, J_(d)=8.0,J_(t)=1.3 Hz, 1H, H-4′), 4.33 (t, J=6.1 Hz, 2H, CH₂CH₂CH₂O), 2.45 (t,J=7.0 Hz, 2H, NCH₂CH₂CH₂), 2.42-2.29 (br s, 8H, piperazinyl methylene),2.15 (s, 3H, CH₃N), 1.92 (quintet, J=6.7 Hz, 2H, CH₂CH₂CH₂).

Analysis calculated for C₂₂H₂₅BrN₆O₃.3HCl.H₂O requires: C, 42.0; H, 4.8;N, 13.4; Cl, 16.9%. Found: C, 42.1; H, 4.5; N, 13.3; Cl, 16.9%.

Freshly washed (1N HCl then distilled H₂O) iron powder (4 mol eq., 0.138g) was added in portions to a refluxing solution of the abovenitroquinazoline (0.31 g, 0.62 mmol) in EtOH/H₂O (2:1, 50 mL) containingglacial acetic acid (1.0 mL). The resulting suspension was heated atreflux with vigorous stirring for 20 minutes then cooled, basified bythe addition of concentrated NH₃, and filtered through a pad of celite.The celite pad was washed with EtOH before the filtrate was concentratedunder reduced pressure, diluted with water, and extracted with EtOAc.The combined organic extracts were dried over anhydrous Na₂SO₄,concentrated under reduced pressure and chromatographed on Grade IIIalumina, eluting with MeOH/EtOAc (5:95), to give6-amino-4-[(3-bromophenyl)amino]-7-[3-N-(4-methyl-piperazinyl)propyloxy]quinazoline(238 mg, 82%) as a cream powder, mp (CH₂Cl₂) 171-172° C.

¹H NMR [(CD₃)₂SO]: δ9.36 (s, 1H, NH), 8.38 (s, 1H, H2), 8.22 (t, J=1.9Hz, 1H, H-2′), 7.86 (ddd, J=8.2, 0.8, 1.9 Hz, 1H, H-6′), 7.40 (s, 1H,H5), 7.30 (t, J=8.0 Hz, 1H, H-5′), 7.20 (ddd, J=8.3, 1.0, 1.9 Hz, 1H,H-4′), 7.09 (s, 1H, H8), 5.34 (s, 2H, NH₂), 4.19 (t, J=6.2 Hz, 2H,CH₂CH₂CH₂O), 2.49 (obscured t, J=7 Hz, 2H, NCH₂CH₂CH₂), 2.43-2.29 (br s,8H, piperazinyl methylene), 2.16 (s, 3H, CH₃N), 1.97 (quintet, J=6.8 Hz,2H, CH₂CH₂CH₂).

Analysis calculated for C₂₂H₂₇BrN₆O.1.25H₂O requires: C, 53.5; H, 6.0;N, 17.0%. Found: C, 53.5; H, 5.7; N, 17.0%.

Acrylic acid (6 mol, 2.84 mmol, 195 μL) and Et₃N (excess, 1.0 mL) in DMA(20 mL) under N₂ was added to a stirred solution of the aboveaminoquinazoline (223 mg, 0.47 mmol), and1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI.HCl)(3 mol, 1.42 mmol, 273 mg). The standard procedure above was followed togive after chromatography on Grade III alumina eluting with EtOAc/hexane(1:1) to MeOH/EtOAc (2:98),N-[4-[(3-bromophenyl)amino]-7-[3-N-(4-methyl-piperazinyl)propyloxy]quinazolin-6-yl]acrylamide(145 mg, 58%) as a cream powder, mp (CH₂Cl₂/Et₂O/hexane) 105-107° C.

¹H NMR [(CD₃)₂SO]: δ9.78 (s, 1H, CONH), 9.61 (s, 1H, NH), 8.89 (s, 1H,H5), 8.56 (s, 1H, H2), 8.17 (t, J=1.9 Hz, 1H, H-2′), 7.87 (br d, J=8.5Hz, 1H, H-6′), 7.34 (t, J=8.1 Hz, 1H, H-5′), 7.28 (s, 1H, H8), 7.27 (brdt, J_(d)=8 Hz, J_(t)=1 Hz, 1H, H-4′), 6.72 (dd, J=17.0, 10.3 Hz, 1H,CH₂CHCO), 6.32 (dd, J=17.0, 1.9 Hz, 1H, CH₂CHCO), 5.83 (dd, J=10.2, 1.9Hz, 1H, CH₂CHCO), 4.26 (t, J=6.3 Hz, 2H, CH₂CH₂CH₂O), 2.47 (t, J=7.1 Hz,2H, NCH₂CH₂CH₂), 2.42-2.27 (br s, 8H, piperazinyl methylene), 2.15 (s,3H, CH₃N), 1.98 (quintet, J=6.7 Hz, 2H, CH₂CH₂CH₂).

Analysis calculated for C₂₅H₂₉BrN₆O₂.0.5H₂O requires: C, 56.2; H, 5.7;N, 15.7%. Found: C, 56.3; H, 5.6; N, 15.5%.

EXAMPLE 25N-[4-[(3-Bromophenyl)amino]-7-[3-(1,N-imidazyl)propoxy]quinazolin-6-acrylamide

To a suspension of hexane-prewashed sodium hydride (5.50 mmol, 220 mg ofa 60% dispersion in mineral oil) in THF (20 mL) was cannulated asolution of 3-N-(imidazoyl)propan-1-ol (4.84 mmol, 0.61 g) in THF (30mL). The resulting suspension was stirred at 20° C. under N₂ for 2 hoursduring which time the required sodium alkoxide partially precipitatedfrom solution, Solid4-[(3-bromophenyl)amino]-7-fluoro-6-nitro-quinazoline [J Med Chem,1996(39):918] (0.80 g, 2.20 mmol) was then added to this suspension togive a dark red solution which was heated at reflux for 24 hours beforebeing diluted with water and extracted with EtOAc. The combined organicextracts were dried over anhydrous Na₂SO₄, concentrated under reducedpressure and chromatographed on silica gel eluting with CH₂Cl₂/EtOAc(1:1) to MeOH/CH₂Cl₂/EtOAc (3:7:10),4-[(3-bromophenyl)amino]-7-[3-N-(imidazoyl)propyloxy]-6-nitroquinazoline(524 mg, 51%) as a yellow powder, mp (CH₂Cl₂/hexane) 212-215° C.

¹H NMR [(CD₃)₂SO]: δ10.16 (s, 1H, NH), 9.30 (s, 1H, H5), 8.70 (s, 1H,H2), 8.19 (t, J=1.6 Hz, 1H, H-2′), 7.88 (dt, J_(d)=7.8 Hz, J_(t)=1.5 Hz,1H, H-6′), 7.63 (s, 1H, imidazoyl methine), 7.48 (s, 1H, H8), 7.39 (t,J=7.9 Hz, 1H, H-5′), 7.35 (dt, J_(d)=8.0 Hz, J_(t)=1.6 Hz, 1H, H-4′),7.21 (s, 1H, imidazoyl methine), 6.90 (s, 1H, imidazoyl methine), 4.22(t, J=6.0 Hz, 2H, CH₂CH₂CH₂), 4.18 (t, J=6.8 Hz, 2H, CH₂CH₂CH₂), 2.26(quintet, J=6.4 Hz, 2H, CH₂CH₂CH₂).

Analysis calculated for C₂₀H₁₇BrN₆O₃ requires: C, 51.2; H, 3.6; N,17.9%. Found: C, 51.0; H, 3.6; N, 17.6%.

Freshly washed (1N HCl then distilled H₂O) iron powder (4 mol, 0.241 g)was added in portions to a refluxing solution of the above6-nitroquinazoline (0.51 g, 1.08 mmol) in EtOH/H₂O (2:1, 60 mL)containing glacial acetic acid (0.7 mL). Identical reaction procedureand workup as in the previous example gave, after chromatography onGrade III alumina eluting with MeOH/EtOAc (5:95),6-amino-4-[(3-bromophenyl)-amino]-7-[3-N-(imidazoyl)propyloxy]quinazoline(389 mg, 82%) as a off-white powder, mp (CH₂Cl₂/Et₂O) 178-180° C.

¹H NMR [(CD₃)₂SO]: δ9.37 (s, 1H, NH), 8.38 (s, 1H, H2), 8.22 (t, J=1.8Hz, 1H, H-2′), 7.86 (br d, J=8.1 Hz, 1H, H-6′), 7.66 (s, 1H, imidazoylmethine), 7.40 (s, 1H, H5), 7.30 (t, J=8.1 Hz, 1H, H-5′), 7.23 (s, 1H,imidazoyl methine), 7.21 (br d, J=7.7 Hz, 1H, H-4′), 7.06 (s, 1H, H8),6.90 (s, 1H, imidazoyl methine), 5.45 (s, 2H, NH₂), 4.28 (t, J=7.1 Hz,2H, CH₂CH₂CH₂), 4.10 (t, J=5.8 Hz, 2H, CH₂CH₂CH₂), 2.27 (quintet, J=6.5Hz, 2H, CH₂CH₂CH₂).

Analysis calculated for C₂₀H₁₉BrN₆O.0.5H₂O requires: C, 53.6; H, 4.5; N,18.7%. Found: C, 53.6; H, 4.5; N, 18.6%.

To a stirred solution of6-amino-4-[(3-bromo-phenyl)amino]-7-[3-N-(imidazoyl)propyloxy]quinazoline(383 mg, 0.87 mmol), acrylic acid (6 mol, 5.23 mmol, 359 μL), andpyridine (excess, 1.0 mL) in DMA (20 mL) under N₂ was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl)(5 mol, 4.36 mmol, 838 mg). The standard procedure above was followed togive after chromatography on Grade III alumina eluting with EtOAc/hexane(1:1) to MeOH/EtOAc (5:95),N-[4-[(3-bromophenyl)amino]-7-[3-N-(imidazoyl)-propyloxy]quinazolin-6-acrylamide(9 mg, 2%) as a cream powder, mp (CH₂Cl₂/Et₂O/hexane) 235-237° C.

¹H NMR [(CD₃)₂SO]: δ9.79 (s, 1H, CONH), 9.60 (s, 1H, NH), 8.88 (s, 1H,H5), 8.55 (s, 1H, H2), 8.18 (t, J=1.9 Hz, 1H, H-2′), 7.87 (ddd, J=8.2,1.8, 1.0 Hz, 1H, H-6′), 7.64 (s, 1H, imidazoyl methine), 7.34 (t, J=8.0Hz, 1H, H-5′), 7.28 (br dt, J_(d)=8.0 Hz, J_(t)=1.2 Hz, 1H, H-4′), 7.27(s, 1H, H8), 7.21 (t, J=1.3 Hz, 1H, imidazoyl methine), 6.89 (br s, 1H,imidazoyl methine), 6.73 (dd, J=17.0, 10.2 Hz, 1H, CH₂CHCO), 6.34 (dd,J=17.0, 1.8 Hz, 1H, CH₂CHCO), 5.85 (dd, J=10.2, 1.8 Hz, 1H, CH₂CHCO),4.22 (t, J=6.9 Hz, 2H, CH₂CH₂CH₂), 4.14 (t, J=6.0 Hz, 2H, CH₂CH₂C₂),2.27 (quintet, J=6.4 Hz, 2H, CH₂CH₂CH₂).

Analysis calculated for CH₂₃H₂₁BrN₆O₂.0.75H₂O requires: C, 54.5; H, 4.5;N, 16.6%. Found: C, 54.5; H, 4.4; N, 16.2%.

EXAMPLE 26 N-[4-[(3-Bromophenyl)amino]-7-[4-(N,N-dimethyl-amino]butoxyl]quinazolin-6-yl]acrylamide

To a suspension of hexane prewashed sodium hydride (11.0 mmol, 440 mg ofa 60% dispersion in mineral oil) in THF (20 mL) was cannulated asolution of 4-(N,N-dimethylamino]butan-1-ol (8.80 mmol, 1.03 g) in THF(30 mL). The resulting suspension was stirred at 20° C. under N₂ for 2hours and then cannulated into a solution of4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline (J Med Chem,1996;39:918-928) (0.80 g, 2.20 mmol) in THF (30 mL) under N₂. The darkred solution was then heated at reflux overnight. Identical workup asabove gave, after chromatography on grade III alumina eluting with EtOActo MeOH/EtOAc (5:95) to give6-amino-4-[(3-bromophenyl)amino]-7-[4-(N,N-dimethylamino)butyloxy]quinazoline(310 mg, 33%) as a pale brown powder, mp (CH₂Cl₂/hexane) 155-156° C.

¹H NMR [(CD₃)₂SO], (400 MHz): δ9.36 (s, 1H, NH), 8.39 (s, 1H, aromatic),8.23 (t, J=2.0 Hz, 1H, H-2′), 7.86 (br d, J=8.0 Hz, 1H, H-6′), 7.41 (s,1H, aromatic), 7.30 (t, J=8.1 Hz, 1H, H-5′), 7.20 (ddd, J=8.2 Hz, J=0.8Hz, J=1.8 Hz, 1H, H-4′), 7.09 (s, 1H, aromatic), 5.32 (s, 2H, NH₂), 4.17(t, J=6.2 Hz, 2H, CH₂CH₂CH₂CH₂O), 2.47 (t, J=7.3 Hz, 2H, NCH₂CH₂CH₂CH₂),2.15 (s, 6H, N(CH₃)₂), 1.84 (quintet, J=6.4 Hz, 2H, CH₂CH₂CH₂CH₂), 1.62(quintet, J=6.9 Hz, 2H, CH₂CH₂CH₂CH₂).

Analytical calculated for C₂₀H₂₄BrN₅O.^(½) H₂O requires: C, 54.7; H,5.7; N, 15.9%. Found: C, 54.3; H, 5.8; N, 15.8%.

To a stirred solution of the above 6-aminoquinazoline (276 mg, 0.64mmol), acrylic acid (6 mol eq., 3.85 mmol, 264 mL), and Et₃N (excess,1.0 mL) in DMA (10 mL) under N₂ was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl)(3 mol eq., 1.92 mmol, 369 mg). The standard procedure above wasfollowed to give after chromatography on grade III alumina eluting withEtOAc/hexane (1:1) to MeOH/EtOAc (3:97),N-[4-[(3-bromophenyl)amino]-7-[4-(N,N-dimethylamino)butyloxy]-quinazolin-6-yl]acrylamide(98 mg, 32%) as a cream powder, mp (CH₂Cl₂/Et₂O) 112-115° C.

¹H NMR [(CD₃)₂SO], (400 MHz): δ9.77 (s, 1H, CONH), 9.62 (s, 1H, NH),8.88 (s, 1H, aromatic), 8.56 (s, 1H, aromatic), 8.17 (t, J=1.9 Hz, 1H,H-2′), 7.87 (ddd, J=8.2 Hz, J=1.8 Hz, J=1.0 Hz, 1H, H-6′), 7.34 (t,J=8.0 Hz, 1H, H-5′), 7.29 (s, 1H, aromatic), 7.27 (ddd, J=8.2 Hz, J=1.8Hz, J=1.0 Hz, 1H, H-4′), 6.71 (dd, J=17.1 Hz, J=10.2 Hz, 1H, CH₂CHCO),6.32 (dd, J=17.0 Hz, J=1.9 Hz, 1H, CH₂CHCO), 5.82 (dd, J=10.2 Hz, J=1.9Hz, 1H, CH₂CHCO), 4.24 (t, J=6.6 Hz, 2H, CH₂CH₂CH₂CH₂O), 2.27 (t, J=7.2Hz, 2H, NCH₂CH₂CH₂CH₂), 2.12 (s, 6H, N(CH₃)₂), 1.85 (quintet, J=6.9 Hz,2H, CH₂CH₂CH₂CH₂), 1.60 (quintet, J=7.4 Hz, 2H, CH₂CH₂CH₂CH₂).

Analysis calculated for C₂₃H₂₆BrN₅O₂.1.25 H₂O requires: C, 54.5; H, 5.7;N, 13.8%. Found: C, 54.5; H, 5.3; N, 13.7%.

EXAMPLE 27N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-N-[3-morpholinopropyl]acrylamide

A stirred solution ofN-[4-[(3-bromophenyl)amino]-quinazolin-6-yl]acrylamide (1.78 g, 4.82mmol), morpholine (excess, 4.0 mL) and p-toluenesulfonic acid(catalytic) in THF (50 mL) was heated at 50° C. for 4 hours before beingconcentrated under reduced pressure, diluted with water and extractedwith EtOAc. The combined organic extracts were washed with brine, driedover anhydrous Na₂SO₄, concentrated under reduced pressure, andchromatographed on silica gel eluting with MeOH/CH₂Cl₂/EtOAc (15:40:45)to giveN-[4-[(3-bromophenyl)amino]quinazolin-6-yl]-3-morpholino-propylamide(1.86 g, 78%) as a cream powder, mp (EtOAc) 184-186° C.

¹H NMR [(CD₃)₂SO]: δ10.37 (s, 1H, CONH), 9.91 (s, 1H, NH), 8.72 (d,J=1.9 Hz, 1H, H-5), 8.58 (s, 1H, H-2), 8.17 (t, J=2.1 Hz, 1H, H-2′),7.86 (m, 2H, H-7, 6′), 7.78 (d, J=8.9 Hz, 1H, H-8), 7.35 (t, J=8.0 Hz,1H, H-5′), 7.29 (dt, J_(t)=1.2 Hz, J_(d)=8.0 Hz, 1H, H-4′), 3.40 (t,J=4.6 Hz, 4H, morpholino methylene), 2.69 (t, J=6.6 Hz, 2H,NCH₂CH₂CONH), 2.58 (t, J=6.6 Hz, 2H, NCH₂CH₂CONH), 2.44 (br s, 4H,morpholino methylene).

¹³C NMR: δ170.24, 157.18, 152.86, 146.48, 141.13, 136.87, 130.21,128.39, 127.01, 125.74, 124.21, 121.03, 120.79, 115.40, 111.46, 66.09(×2), 54.04, 53.00 (×2), 33.66.

Analysis calculated for C₂₁H₂₂BrN₅O₂ requires: C, 55.3; H, 4.9; N,15.3%. Found: C, 55.1; H, 5.2; N, 15.2%.

To a stirred solution of the above amide (0.85 g, 1.86 mmol) in THF (30mL) under N₂ at 0° C. was added BH₃.DMS (2 mol eq., 372 μL of a 10 Msolution) dropwise. The resulting solution was allowed to warm to 25° C.and was stirred for 2 hours before being quenched by the cautiousaddition of 1N HCl (40 ML). The reaction mixture was then stirred at 50°C. for 2 hours, basified by the addition of saturated Na₂CO₃, andextracted with EtOAc. The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure,and chromatographed on silica gel eluting with MeOH/CH₂Cl₂/EtOAc (3:8:8)to give4-[(3-bromophenyl)-amino]-6-[(3-morpholinopropyl)amino]quinazoline (130mg, 16%) as a yellow glass (ca. 90% pure by NMR). This was used withoutfurther purification.

¹H NMR [(CD₃)₂SO]: δ9.40 (s, 1H, NHAr), 8.37 (s, 1H, H-2), 8.17 (t,J=1.9 Hz, 1H, H-2′), 7.91 (br d, J=8.2 Hz, 1H, H-6′), 7.54 (d, J=9.0 Hz,1H, H-8), 7.34 (t, J=8.0 Hz, 1H, H-5′), 7.27 (m, 2H, H-4′, 7), 7.16 (d,J=2.2 Hz, 1H, H-5), 6.25 (t, J=5.1 Hz, 1H, CH₂NH), 3.59 (t, J=4.5 Hz,4H, morpholino methylene), 3.22 (q, J=6.0 Hz, 1H, CH₂NH), 2.45 (t, J=6.9Hz, 2H, CH₂CH₂CH₂NH), 2.39 (br s, 4H, morpholino methylene), 1.82(quintet, J=7.0 Hz, 2H, CH₂CH₂CH₂).

To a stirred solution of the above amine (133 mg, 0.30 mmol), acrylicacid (4 mol eq., 1.20 mmol, 83 μL), and Et₃N (excess, 0.5 mL) in DMF(5.0 mL) under N₂ was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl)(2.0 mol, 0.60 mmol, 115 mg). The standard procedure above was followedto give, after chromatography on silica gel eluting with EtOAc:CH₂Cl₂(1:1) to MeOH/CH₂Cl₂/EtOAc (3:7:10),N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]-N-[3-morpholinopropyl]acrylamide(39 mg, 26%) as a cream powder, mp (CH₂Cl₂/hexane) 171-175° C.

¹H NMR [(CD₃)₂SO]: δ9.86 (s, 1H, NH), 8.70 (s, 1H, H-2), 8.52 (d, J=2.0Hz, 1H, H-5), 8.20 (t, J=1.9 Hz, 1H, H-2′), 7.91 (br d, J=8.6 Hz, 1H,H-6′), 7.89 (d, J=8.9 Hz, 1H, H-8), 7.79 (dd, J=8.8 Hz, J=2.1 Hz, 1H,H-7), 7.38 (t, J=7.9 Hz, 1H, H-5′), 7.33 (dt, J_(d)=8.4 Hz, J_(t)=1.7Hz, 1H, H-4′), 6.22 (dd, J=16.7, 2.3 Hz, 1H, CH₂CHCO), 6.05 (br s, 1H,CH₂CHCO), 5.61 (br d, J=8.8 Hz, 1H, CH₂CHCO), 3.87 (t, J=7.4 Hz, 2H,CH₂NRCO), 3.49 (t, J=4.5 Hz, 4H, morpholino methylene), 2.28 (t, J=7.1Hz, 2H, CH₂CH₂CH₂NRCO), 2.27 (br s, 4H, morpholino methylene), 1.69(quintet, J=7.3 Hz, 2H, CH₂CH₂CH₂).DEI HRMS (M⁺).

Calculated for C₂₄H₂₆Br⁸¹N₅O₂: 497.1249 Found: 497.1250.

EXAMPLE 28 N-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]propanamide

To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (157 mg,0.5 mmol) in dry THF (3 mL) stirred under N₂ at 25° C. was addeddropwise propionyl chloride (0.05 mL, 0.58 mmol). A yellow solid formedat once. After 45 minutes the solid was collected by filtration andwashed with ether and dried. Recrystallized from wet methanol affordedthe desired product (97 mg, 47%), mp 265-266° C.

¹H NMR [(CD₃)₂SO]: δ11.3 (brs, 1H, NH), 10.53 (s, 1H, NH), 9.02 (s, 1H,H5), 8.88 (s, 1H, H2), 8.00-7.97 (m, 2H, H7, H2′), 7.89 (d, J=9.1 Hz,1H, H8), 7.71(d, J=7.8 Hz, 1H, H6′), 7.50 (d, J=8.3 Hz, 1H, H4′), 7.45(t, J=8.1 Hz, 1H, H5′), 2.45 (q, J=7.3 Hz, 2H, CH₂), 1.15 (t, J=7.5 Hz,3H, CH₃). Mass Spectrum (CI): 373 (84, ⁸¹BrMH⁺), 372 (43, ⁸¹BrM⁺), 371(100, ⁷⁹BrMH⁺), 370 (28, ⁷⁹BrM⁺).

Calculated for C₁₇H₁₅N₄BrO.HCl..0.5H₂O: C, 49.00; H, 4.11; N, 13.45%.Found: C, 48.89; H, 3.97; N, 13.36%.

EXAMPLE 29 N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-methacrylamide

To a stirred solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (JMed Chem, 1995;38:3482) (0.50 g, 1.59 mmol) in THF (20 mL) undernitrogen was added Et₃N (excess, 1.0 mL), a catalytic amount of DMAP andmethacryloyl chloride (1.1 mol eq., 1.75 mmol, 171 μL) dropwise. Thereaction was stirred at 25° C. for 1.5 hours over which time two furtheramounts (50 μL) of methacryloyl chloride were added. The reaction wasthen diluted with saturated NaHCO₃ and extracted with EtOAc. Thecombined organic extracts were dried over anhydrous Na₂SO₄, concentratedunder reduced pressure and chromatographed on silica gel eluting withCH₂Cl₂/EtOAc (1:1) to MeOH/CH₂Cl₂/EtOAc (5:45:50). Recrystallizationfrom EtOAc gaveN-[4-[(3-bromophenyl)amino]quinazolin-6-yl]-2-methylacrylamide (195 mg,32%) as a cream powder, mp 244-245° C.

¹H NMR [(CD₃)₂SO]: δ10.15 (s, 1H, CONH), 9.90 (s, 1H, NH), 8.80 (br s,1H, H-5), 8.60 (s, 1H, H-2), 8.20 (br s, 1H, H-2′), 7.97 (br d, J=8.6Hz, 1H, H-7), 7.89 (br d, J=7.7 Hz, 1H, H-6′), 7.80 (d, J=8.9 Hz, 1H,H-8), 7.35 (t, J=8.0 Hz, 1H, H-5′), 7.30 (br d, J=7.5 Hz, 1H, H-4′),5.94 (s, 1H, CH₂C(CH₃)CO), 5.62 (s, 1H, CH₂C(CH₃)CO), 2.02 (s, 3H,CH₂C(CH₃)CO). ¹³C NMR: δ166.71, 157.17, 153.07, 146.69, 141.09, 139.93,136.62, 130.23, 128.24, 128.11, 125.73, 124.11, 121.04, 120.66, 120.51,115.19, 113.28, 18.60.

Analysis calculated for C₁₈H₁₅BrN₄O requires: C, 56.4; H, 4.0; N, 14.6%.Found: C, 56.1; H, 3.9; N, 14.5%.

EXAMPLE 30N-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]ethenyl-sulfonamide

To a stirred solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (JMed Chem, 1995;38:3482) (0.30 g, 0.95 mmol) in THF (20 mL) undernitrogen was added Et₃N (3.5 mol eq., 3.33 mmol, 245 μL), a catalyticamount of DMAP and chloroethanesulfonyl chloride (1.2 mol eq., 1.14mmol, 119 μL) dropwise. The reaction was stirred at 25° C. for 1 hourand then diluted with saturated NaHCO₃ and extracted with EtOAc. Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, concentrated under reduced pressure, and chromatographed onsilica gel eluting with MeOH/CH₂Cl₂/EtOAc (3:47:50). Crystallizationfrom CH₂Cl₂/hexane gaveN-[4-[(3-bromophenyl)amino]-quinazolin-6-yl]vinylsulfonamide (210 mg,54%) as a cream powder, mp 217° C. (dec).

¹H NMR [(CD₃)₂SO]: δ10.31 (s, 1H, SO₂NH), 9.96 (s, 1H, NH), 8.60 (s, 1H,H-2), 8.20 (d, J=2.0 Hz, 1H, H-5), 8.14 (br s, 1H, H-2′), 7.85 (br d,J=7.9 Hz, 1H, H-6′), 7.81 (d, J=8.9 Hz, 1H, H-8), 7.67 (dd, J=8.9, 2.1Hz, 1H, H-7), 7.37 (t, J=8.0 Hz, 1H, H-5′), 7.32 (br d, J=8.1 Hz, 1H,H-4′), 6.90 (dd, J=16.4, 9.8 Hz, 1H, CH₂CHSO₂), 6.17 (d, J=16.4 Hz, 1H,CH₂CHSO₂), 6.06 (d, J=9.8 Hz, 1H, CH₂CHSO₂).

¹³C NMR: δ157.18, 153.47, 147.17, 140.83, 136.02, 135.48, 130.25,129.03, 128.44, 127.77, 126.08, 124.60, 121.18, 121.03, 115.43, 114.01.

Analysis calculated for C₁₆H₁₃BrN₄O₂S requires: C, 47.4; H, 3.2; N,13.8%. Found: C, 47.7; H, 3.1; N, 13.8%.

EXAMPLE 31 N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E-but-2-enamide

To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg,1.0 mmol) in THF (6 mL) stirred under N₂ at 0° C. was addedtrans-crotonyl chloride. A yellow solid formed upon addition. The solidwas collected by Buchner filtration after 2.5 hours and sonicated withEtOAc to give the title compound (216 mg, 52%), mp 279-281° C.

¹H NMR [(CD₃)₂SO]: δ11.55 (brs, 1H, NH), 10.78 (s, 1H, NH), 9.17 (d,J=1.9 Hz, 1H, H5), 8.97 (s, 1H, H2), 8.12 (dd, J=9.1, 2.0 Hz, 1H, H7),8.05 (t, J=1.9 Hz, 1H, H2′), 7.99 (d, J=9.0 Hz, 1H, H8), 7.76 (dd,J=8.1, 2.0 Hz, 1H, H6′), 7.58 (dd, J=8.6, 1.7 Hz, 1H, H4′), 7.52 (t,J=8.1 Hz, 1H, H5′) 7.03-6.94 (m, 1H, [(CO)CH═], 6.34 (dd, J=15.1, 1.7Hz, 1H, CH═CHCH₃), 1.98 (dd, J=6.8, 1.4 Hz, 3H, CH₃).

Mass Spectrum (CI): 385 (89, ⁸¹BrMH⁺), 384 (51, ⁸¹BrM⁺), 383 (100,⁷⁹BrMH⁺), 382 (37, ⁷⁹BrM⁺). Calculated for C₁₈H₁₅N₄BrO.HCl: C, 51.51; H,3.84; N, 13.35%. Found: C, 51.29; H, 3.52; N, 13.13%.

EXAMPLE 32N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-4,4,4-trifluoro-E-but-2-enamide

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg, 1.0mmol) was added to a solution of6-amino-4[(3-bromophenyl)amino]quinazoline (158 mg, 0.5 mmol) and4,4,4,-trifluorobut-2-enoic acid (153 mg, 1.1 mmol) in THF/DMF (4:1, 2.5mL), stirred under nitrogen at 0° C. After 1 hour water (10 mL) wasadded and after 15 minutes the precipitate was collected by Buchnerfiltration. The residue was rinsed with water (2×5 mL) and ether (10 mL)and air dried. The solid was suspended in EtOAc, (10 mL) refluxedbriefly, and sonicated for 10 minutes, and the solid was collected byBuchner filtration, rinsed with EtOAc (5 mL) and dried in a vacuum ovenat 75° C. for 1.5 hours to giveN-[4-[(3-bromophenyl)amino]-quinazolin-6-yl]4,4,4-trifluorobut-2-enamide0.4 hydrochloride (76 mg, 33%) as a light yellow solid, mp 273-278° C.

Calculated for C₁₈H₁₃BrF₃N₄O.0.4 HCl: C, 47.85; H, 2.77;.N, 12.40%.Found: C, 47.89, H, 2.66; N, 12.27%.

¹H NMR [(CD₃)₂SO]: δ11.09 (brs, 1H, NH), 10.43 (s, 1H, NH), 8.90 (s, 1H,H2), 8.70 (s, 1H, H5), 8.11 (s, 1H, H2′), 7.97 (dd, J=2.5, 9.2 Hz, 1H,H7), 7.87 (d, J=9.0 Hz, 1H, H8), 7.81 (d, J=6.9 Hz, 1H, H6′), 7.41-7.33(m, 2H, H5′ & H4′), 7.11 (d, J=16.4 Hz, 1H, CH═CHCF₃), 7.03 (dq,J_(d)=16.4 Hz, J_(q)=6.4 Hz, 1H, CH═CHCF₃).

Mass Spectrum (CI) 439 (78 ⁸¹BrM⁺), 437 (100 ⁷⁹BrM⁺).

EXAMPLE 33 N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-propynamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (200 mg,1.04 mmol) was added to a solution of6-amino-4-[(3-bromophenyl)-amino]quinazoline (158 mg, 0.5 mmol) andpropiolic acid (0.08 mL, 1.1 mmol) in DMF (1.5 mL) stirred under N₂ at0° C. The resulting solution was stirred at 0° C. for 30 minutes andquenched with water. The formed fine solid was collected by Buchnerfiltration then dissolved in methanol and purified by preparative tlc onsilica, eluting with 10% MeOH/CHCl₃. The title compound was isolated asa yellow solid (21 mg, 12%), mp>310° C.

¹H NMR [(CD₃)₂SO]: δ11.18 (brs, 1H, NH), 9.94 (s, 1H, NH), 8.75 (s, 1H,H5), 8.59 (s, 1H, H2), 8.15 (s, 1H, H2′), 7.85-7.79 (m, 3H, H7, H8,H6′), 7.37-7.28 (m, 2H, H5′, H4′), 4.53 (s, 1H, CH). Mass Spectrum (CI):369 (47, ⁸¹BrMH⁺), 368 (24, ⁸¹BrM⁺), 367 (50, ⁷⁹BrMH⁺), 366 (13,⁷⁹BrM⁺), 91 (100).

Calculated for C₁₇H₁₁N₄BrO: C, 55.61; H, 3.02; N, 15.26%. Found: C,55.40; H, 2.84; N, 15.18%.

EXAMPLE 34 N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]but-2-ynamide

To a solution of 2-butynoic acid (196 mg, 2.3 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (385 mg, 2.0mmol) in DMF (5 mL) stirring at 25° C. for 20 minutes was added6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg, 1.0 mmol). Theresulting solution was stirred under N₂ at 25° C. for 14 hours further1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (206 mg, 1.0mmol) and 2-butynic acid (82 mg, 1.0 mmol) were. After another 8 hoursfurther, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(197 mg, 1.0 mmol) and the acid (93 mg, 1.0 mmol) were added to thereaction. After stirring at 25° C. a further 12 hours, the reaction wasquenched with water. The yellow precipitate was collected, sonicatedwith acetone, treated with triethyl amine and purified by preparativetlc on silica, eluting with 1:1 EtOAc/acetone. The desired product wasisolated as a yellow solid (20 mg, 4.7%), mp 281-283° C.

¹H NMR [(CD₃)₂SO]: δ10.97 (brs, 1H, NH), 9.93 (s, 1H, NH), 8.76 (s, 1H,H5), 8.57 (s, 1H, H2), 8.14 (s, 1H, H2′), 7.84-7.76 (m, 3H, H7, H8,H4′), 7.34 (t, J=8.1 Hz, 1H, H5′), 7.29 (d, J=7.8 Hz, 1H, H6′), 2.09 (s,3H, CH₃).

Mass Spectrum (APCI): 383 (100, ⁸¹BrMH^(+),) 382 (23, ⁸¹BrM⁺), 381 (95,⁷⁹BrMH⁺).

Calculated for C₁₈H₁₃N₄BrO.0.3HCl.0.6C₃H₆O: C, 55.69; H, 3.99; N,13.12%. Found: C, 55.67; H, 3.96; N, 12.93%.

EXAMPLE 35N-[4-(3-Bromo-phenylamino)-pyrido[4,3-d]pyrimidin-7-yl]-acrylamide

To a stirred solution of 7-amino-4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidine (J Med Chem, 1995;38:3780)(140 mg, 0.46 mmol), DMAP (14 mg) and Et₃N (excess, 2.0 mL) at 0° C.under N₂ was added acryloyl chloride (4.8 mol eq., 182 μL) dropwise over4 hours. The reaction was then stirred at 20° C. diluted with water andextracted with EtOAc. The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure before being chromatographed on silica gel eluting withMeOH/CH₂Cl₂/EtOAc (5:45:50), to giveN-[4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidin-7-yl]-acrylamide (12mg, 7%) as a cream powder, mp (CH₂Cl₂/hexane) 215-220° C. (dec).

1H NMR [(CD₃)₂SO]: δ11.15 (s, 1H, CONH), 10.25 (s, 1H, NH), 9.67 (s, 1H,H5), 8.71 (s, 1H, H2), 8.40 (s, 1H, H8), 8.21 (t, J=1.9 Hz, 1H, H-2′),7.88 (dt, J_(d)=7.6 Hz, J_(t)=1.5 Hz, 1H, H-6′), 7.38 (t, J=7.7 Hz, 1H,H-5′), 7.36 (dt, J_(d)=7.7 Hz, J_(t)=1.5 Hz, 1H, H-4′), 6.68 (dd,J=17.1, 10.2 Hz, 1H, CH₂CHCO), 6.39 (dd, J=17.0, 1.8 Hz, 1H, CH₂CHCO),5.86 (dd, J=10.1, 1.8 Hz, 1H, CH₂CHCO).

EXAMPLE 36N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide

A suspension of 6-fluoropyrido[3,4-d]pyrimidine-4(3H)-one (U.S. patentapplication Ser. No. 08/358,352, 1994) (1.65 g) in 50 mL thionylchloride and several drops of dimethyl formamide was heated under refluxuntil a clear solution was obtained (20 minutes), and then for a further30 minutes. The volatiles were removed under reduced pressure, and theresidue was dissolved in dichloromethane and washed with aqueous Na₂CO₃.The solvent was dried and removed to give crude4-chloro-6-fluoropyrido[3,4-d]pyrimidine which was dissolved in2-propanol (50 mL) containing 3-bromoaniline (2.1 g). The mixture washeated under reflux for 15 minutes to give a precipitate, which wasredissolved by the addition of triethylamine. After the addition ofwater, the solution was concentrated and cooled to give4-[(3-bromophenyl)amino]-6-fluoropyrido[3,4-d]-pyrimidine, (2.29 g), mp(MeOH) 219.5-221° C.

A mixture of 4-[(3-bromophenyl)amino]-6-fluoro-pyrido[3,4-d]pyrimidine(0.48 g) and 4-methoxybenzyl-amine (10.3 g) in ethanol (50 mL) washeated to 100° C. for 5 days. The resulting product was chromatographedon silica gel, eluting with CH₂Cl₂:EtOAc (3:1), to give4-[(3-bromophenyl)amino]-6-[(4-methoxyphenyl)methyl-amino]pyrido[3,4-d]pyrimidine (0.18 g,) mp (aqueous methanol),178-179.5° C. A 0.10 g portion of this was dissolved in 5 mLtrifluoroacetic acid and heated under reflux for 1 hour, and the mixturewas evaporated to dryness. The residue was partitioned between EtOAc andaqueous ammonia, and the crude product was chromatographed on alumina,eluting with CH₂Cl₂:MeOH (97:3) to give6-amino-4-[(3-bromophenyl)amino]pyrido-[3,4-d]pyrimidine (0.040 g,), mp(CH₂Cl₂) 241.5-242° C.

To a solution of6-amino-4-[(3-bromophenyl)amino]-pyrido[3,4-d]pyrimidine (J Med Chem,1996;39:1823) (455 mg, 1.50 mmol) in dry THF (50 mL) at 0° C. under N₂was added Et₃N (22.5 mmol, 1.61 mL), a catalytic amount of DMAP (45 mg)and acryloyl chloride (4.50 mmol, 366 μL). The reaction mixture wasstirred for 1 hour and then additional acryloyl chloride (100 μL) wasadded and the reaction was allowed to warm to room temperature andstirred for another hour before being worked up as in the previousexample, to give after column chromatography on silica gel eluting withMeOH/EtOAc (5:95),N-[4-[(3-bromophenyl)amino]pyrido-[3,4-d]pyrimidin-6-yl]acrylamide (20mg, 37%) as a cream powder, mp (EtOAc/MeOH) 238-245° C. (dec.).

¹H NMR [(CD₃)₂SO]: δ11.07 (s, 1H, CONH), 10.33 (s, 1H, NH), 9.05 (s, 1H,H5 or H2), 9.03 (s, 1H, H2 or H5), 8.66 (s, 1H, H8), 8.18 (br s, 1H,H-2′), 7.89 (br d, J=7.6 Hz, 1H, H-6′). 7.40-7.33 (m, 2H, H-4′, 5′),6.70 (dd, J=17.0, 10.2 Hz, 1H, CH₂CHCO), 6.41 (dd, J=1.2, 16.9 Hz, 1H,CH₂CHCO), 5.87 (dd, J=1.2, 10.1 Hz, 1H, CH₂CHCO).

¹³C NMR: δ163.35, 156.82, 154.13, 150.87, 147.92, 141.64, 140.40,131.25, 130.26, 127.86, 126.49, 124.76, 121.30, 121.02, 120.97, 103.43.

Analysis calculated C₁₆H₁₂BrN₅O.1.25 H₂O requires: C, 51.3; H, 3.4; N,18.7%. Found: C, 51.1; H, 3.1; N, 18.4%.

EXAMPLE 37 N-[4-(3-Methyl-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]acrylamide

To a stirred solution of6-amino-4-[(3-methylphenyl)amino]pyrido[3,4-d]pyrimidine, made fromm-toluidine and 4-chloro-6-fluoropyrido[3,4-d]-pyrimidine, followed byp-methoxybenzylamine and trifluoroacetic acid, as described in theprevious example (140 mg, 0.56 mmol), DMAP (14 mg) and Et₃N (excess, 0.5mL) at 0° C. under N₂ was added acryloyl chloride (2.7 mol eq., 123 μL)dropwise over 3 hours. The reaction was then stirred at 20° C. for 1hour, diluted with water and extracted with EtOAc. The combined organicextracts were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure before being chromatographed onsilica gel eluting with CH₂Cl₂/EtOAc (1:1) to MeOH/CH₂Cl₂/EtOAc(2:48:50), to giveN-[4-[(3-methylphenyl)amino]pyrido-[3,4-d]pyrimidin-6-yl]acrylamide (41mg, 24%) as a cream powder, mp (EtOAc/hexane) 221-223° C. (decomp).

¹H NMR [(CD₃)₂SO]: δ11.03 (s, 1H, CONH), 10.18 (s, 1H, NH), 9.02 (s, 1H,H5 or H2), 9.01 (s, 1H, H2 or H5), 8.59 (s, 1H, H8), 7.63 (m, 2H, H-2′,6′), 7.29 (m, 1H, H-5′), 6.89 (br d, J=7.5 Hz, 1H, H-4′), 6.69 (dd,J=17.0, 10.2 Hz, 1H, CH₂CHCO), 6.37 (dd, J=17.0, 1.9 Hz, 1H, CH₂CHCO),5.85 (dd, J=10.2, 1.9 Hz, 1H, CH₂CHCO), 2.35 (s, 3H, CH₃Ar).

Analysis calculated for C₁₇H₁₅N₅O requires: C, 66.9; H, 5.0; N, 22.9%.Found: C, 67.3; H, 5.2; N, 22.9%.

EXAMPLE 38N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-methylacrylamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (294 mg, 1.5mmol) was added in one portion to a solution of4-[3-bromophenyl)amino]-6-methylaminopyrido[3,4-d]pyrimidine (100 mg,0.3 mmol), redistilled acrylic acid (75 μL, 1.05 mmol), pyridine, (0.3mL) in 3:2 THF:DMA (1.8 mL) stirred under N₂ at 0° C. After 30 minutesthe reaction was warmed to 25° C., and after 3.75 hours, further acrylicacid (25 μL) was added, and the solution was stirred for an additional 3hours. The solution was quenched with water, and the solids werecollected and air dried. The solids were triturated in hotdichloromethane:ethyl acetate and collected to leave the product (67 mg,56%), mp 215-223° C. (dec). ¹H NMR [(CD₃)₂SO]: δ10.11 (s, 1H, exchangesD₂O), 9.14 (s, 1 H), 8.80 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 7.91 (brd, J=7.7 Hz, 1H), 7.43-7.36 (m, 2H), 6.36-6.23 (m, 2H), 5.66 (dd, J=9.5,3.0 Hz, 1 H), 3.44 (s, 3H).

CIMS m/z (relative %) 383 (23), 384 (100), 385 (40), 386 (99), 387 (20).

Analysis calculated for C₁₇H₁₄N₅OBr 0.4 H₂O: C, 52.16; H, 3.81; N,17.89. Found: C, 52.25; H, 3.51; N, 17.76.

EXAMPLE 39N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-methacrylamide

To a solution of6-amino-4-[(3-bromophenyl)-amino]pyrido[3,4-d]pyrimidine (J Med Chem,1996;39:1823) (250 mg, 0.82 mmol), Et₃N (excess, 2.0 mL) and DMAP(catalytic) in THF (30 mL) under nitrogen was added methacryloylchloride (3×1.1 mol eq., total of 264 μL), the reaction conditions andwork up were followed as above to give after column and preparativelayer chromatography on silica gel eluting with EtOAc/CH₂Cl₂ (1:1),N-[4-[(3-bromophenyl)amino]-pyrido-[3,4-d]pyrimidin-6-yl]-2-methylacrylamide(18 mg, 6%) as a cream powder, mp (CH₂Cl₂/hexane) 177-178° C.

¹H NMR [(CD₃)₂SO]: δ10.61 (s, 1H, CONH), 10.29 (s, 1H, NH), 9.06 (s, 1H,H5), 8.93 (s, 1H, H2), 8.67 (s, 1H, H8), 8.19 (t, J=1.6 Hz, 1H, H-2′),7.91 (dt, J_(d)=7.6 Hz, J_(t)=1.6 Hz, 1H, H-6′), 7.38 (t, J=7.9 Hz, 1H,H-5′), 7.34 (dt, J_(d)=8.1 Hz, J_(t)=1.4 Hz, 1H, H-4′), 6.04 (s, 1H,CH₂C(CH₃)CO), 5.64 (s, 1H, CH₂C(CH₃)CO), 2.03 (s, 1H, CH₂C(CH₃)CO). EIHRMS (M+) C₁₇H₁₄Br⁸¹N₅O requires 385.0361. Found 385.0360.

EXAMPLE 40N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-ethenylsulfonamide

A solution of 6-amino-4-[(3-bromophenyl)amino]-pyrido[3,4-d]pyrimidine(J Med Chem, 1996;39:1823) (250 mg, 0.82 mmol), Et₃N (0.23 mL) and DMAP(catalytic) in THF (20 mL) was reacted with chloro-ethanesulfonylchloride (1.4 mol eq., 1.15 mmol, 120 μL) as above to give afterchromatography on silica gel eluting with MeOH/CH₂Cl₂/EtOAc (2:48:50)and crystallization from CH₂Cl₂/hexane,N-[4-[(3-bromophenyl)amino]pyrido-[3,4-d]pyrimidin-6-yl]-vinylsulfonamide(53 mg, 16%) as a cream powder, mp 261-265° C.

¹H NMR [(CD₃)₂SO]: δ11.02 (s, 1H, SO₂NH), 10.25 (s, 1H, NH), 9.02 (s,1H, H5), 8.67 (s, 1H, H2), 8.15 (br s, 1H, H-2′), 8.00 (s, 1H, H8), 7.87(dt, J_(d)=7.2 Hz, J_(t)=1.9 Hz, 1H, H-6′), 7.40 (br t, J=7.9 Hz, 1H,H-5′), 7.37 (br dt, J_(d)=7.8 Hz, J_(t)=1.9 Hz, 1H, H-4′), 7.07 (dd,J=16.5, 9.9 Hz, 1H, CH₂CHSO₂), 6.30 (d, J=16.5 Hz, 1H, CH₂CHSO₂), 6.09(d, J=9.9 Hz, 1H, CH₂CHSO₂).

¹³C NMR: δ156.59, 154.34, 151.23, 147.43, 141.54, 140.18, 137.02,130.36, 127.06, 126.73, 124.88, 121.43, 121.24, 121.07, 103.57.

Analysis calculated for C₁₅H₁₂BrN₅O₂S.0.25 H₂O requires: C, 43.9; H,3.1; N, 17.0%. Found: C, 44.2; H, 3.0; N, 16.5%.

EXAMPLE 41N-[4-(3-Bromo-phenylamino)-pyrido[3,2-d]pyrimidin-6-yl]-acrylamide

To a stirred solution of6-amino-4-[(3-bromo-phenyl)amino]pyrido[3,2-d]pyrimidine (J Med Chem,1996;39:1823) (46 mg, 0.15 mmol) and acrylic acid (6 mol eq., 0.91 mmol,62 μL) in DMA (5.0 mL) under N₂ was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl)(4.0 mol eq., 0.61 mmol, 116 mg). The reaction mixture was stirred for48 hours with additional amounts of acrylic acid and EDCI.HCl (62 μL/116mg) being added every 12 hours it was then worked up as above to giveafter chromatography on silica gel eluting with EtOAc:CH₂Cl₂ (1:1) toMeOH/CH₂Cl₂/EtOAc (2:48:50), N-[4-[(3-bromophenyl)-amino]pyrido[3,2-d]pyrimidin-6-yl]acrylamide (14 mg, 26%) as a cream powder, mp(CH₂Cl₂/hexane) 226-228° C.

¹H NMR [(CD₃)₂SO]: δ11.13 (s, 1H, CONH), 9.57 (s, 1H, NH), 8.72 (s, 1H,H2), 8.69 (d, J=9.1 Hz, 1H, H8), 8.43 (t, J=1.9 Hz, 1H, H-2′), 8.30 (d,J=9.1 Hz, 1H, H7), 7.87 (br d, J=6.9 Hz, 1H, H-6′), 7.39 (t, J=8.1 Hz,1H, H-5′), 7.33 (dt, J_(d)=8.2 Hz, J_(t)=1.3 Hz, 1H, H-4′), 6.68 (dd,J=17.0, 10.2 Hz, 1H, CH₂CHCO), 6.43 (dd, J=17.0, 1.8 Hz, 1H, CH₂CHCO),5.91 (dd, J=10.2, 1.8 Hz, 1H, CH₂CHCO).

Analysis calculated for C₁₆H₁₂BrN₅O requires: C, 51.9; H, 3.3; N, 18.9%.Found: C, 51.7; H, 3.3; N, 18.8%.

EXAMPLE 42N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3.2-d]pyrimidin-8yl]acrylamide

To a solution of 8-amino-4-[(3-bromophenyl)amino]benzothieno-pyrimidine[see Patent Application WO 95/19970 1995] (100 mg, 0.26 mmol), acrylicacid (0.04 mL, 0.58 mmol), and triethylamine (0.07 mL, 0.5 mmol) in DMF(1.5 mL) stirred under N₂ at 25° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg,0.66 mmol). After 24 hours the reaction mixture was quenched with waterand the light tan precipitate was collected by Buchner filtration andpurified by preparative tlc on silica, eluting with 10% MeOH/CHCl₃ togive the desired product (25 mg, 23%) as a tan solid, mp 249.0-250.5° C.

¹H NMR [(CD₃)₂SO]: δ10.50 (s, 1H, NH), 9.86 (s, 1H, NH), 8.86 (d, J=2.0Hz, 1H, H9), 8.79 (s, 1H, H2), 8.19 (s, 1H, H2′), 8.17 (dd, J=8.0, 1.9Hz, 1H, H7), 7.91 (dd, J=8.8, 2.2 Hz, 1H, H6), 7.84 (d, J=8.1 Hz, 1H,H6′), 7.35 (t, J=8.1 Hz, 1H, H5′), 7.29 (d, J=8.0 Hz, 1H, H4′), 6.50(dd, J=16.9, 10 Hz, 1H, ═CH), 6.33 (dd, J=16.8, 2.1 Hz, 1H, ═CH2), 5.82(dd, J=10, 1.9 Hz, 1H, ═CH2).

Mass Spectrum (APCI): 427 (100, ⁸¹BrMH⁺), 426 (21, ⁸¹BrM⁺), 425 (93,⁷⁹BrMH⁺).

Calculated for C₁₉H₁₃N₄BrOS.0.3HCl.0.25C₃H₆O: C, 52.49; H, 3.18; N,12.19%. Found: C, 52.62; H, 3.31; N, 12.40%.

EXAMPLE 43N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3,2-d]-pyrimidin-6-yl]acrylamide6-Amino-4-(3-bromoaniline)benzothieno[3,2-d]pyrimidine

2-Chloro-3-nitrobenzamide: DMF (3 drops) was added to a mixture of2-chloro-3-nitrobezoic acid (0.99 g, 4.9 mmol), oxalyl chloride (0.47mL, 5.4 mmol) in CH₂Cl₂ (20 mL) at 25° C. stirring under N₂. After gasformation ceased, all the solid went into solution. After 3 hours thesolvent was removed under reduced pressure to leave a light yellow solidwhich was treated with cold NH₄OH (20 mL). 2-Chloro-3-nitrobenzamide wascollected as an off-white solid (1.02 g, 100%).

¹H NMR [(CD₃)₂SO]: δ8.12 (brs, 1H, NH2), 8.06 (dd, J=8.0, 1.7 Hz, 1H,H4), 7.87 (brs, 1H, NH2), 7.73 (dd, J=7.8, 1.7 Hz, 1H, H6), 7.63 (t,J=8.1 Hz, 1H, H5).

2-Chloro-3-nitrobenzonitrile: A solution of 2-chloro-3-nitrobenzamide(1.02 g, 4.9 mmol) in P₂O₅/(TMS)₂O/1,2-dichloroethane (30 mL) was heatedat 85° C. for 18 hours. After it was cooled to 25° C., the solution wasfiltered through a plug of silica gel (60 mL), eluting with 5%methanol/CHCl₃ (400 mL). The combined washes were concentrated underreduced pressure to give 2-chloro-3-nitrobenzonitrile as an off-whitesolid (0.66 g, 74%).

¹H NMR [(CD₃)₂SO]: δ8.42 (dd, J=8.1, 1.5 Hz, 1H, H4), 8.33 (dd, J=8.1,1.7 Hz, 1H, H6), 7.81 (t, J=8.3 Hz, 1H, H5).

3-Amino-2-methylcarboxylate-7-nitrobenzothiophene: NEt₃ (0.16 mL, 1.15mmol) was added dropwise to a solution of 2-chloro-3-nitrobenzonitrile(191 mg, 1.05 mmol), and methyl thioacetate (0.1 mL, 1.1 mmol) in DMSO(3 mL) at 25° C. stirring under N₂. The color of the solution turneddark orange. Thirty minutes later the reaction was quenched with icewater. The formed solid was collected by Buchner filtration and airdried to give methyl 3-amino-7-nitrobenzothiophene-2-carboxylate as ared-orange solid (244 mg, 92%).

¹H NMR [(CD₃)₂SO]: δ8.67 (dd, J=8.1, 1.0 Hz, 1H, H6), 8.58 (dd, J=7.8,0.8 Hz, 1H, H4), 7.72 (t, J=7.8 Hz, 1H, H5), 7.37 (brs, 2H, NH2).

6-Nitrobenzothieno[3,2-d]pyrimidone: A mixture of methyl3-amino-7-nitrobenzothiophene-2-carboxylate (242 mg, 0.96 mmol) andformamidine acetate (0.51 g, 4.9 mmol) was heated up to 185° C. when 1.5mL formamide was added to the reaction. After 1 hour at 185° C., thereaction was cooled to 25° C. The solid was collected and washed withwater then dried. 6-Nitrobenzothieno [3,2-d]pyrimidone was isolated as ayellow solid (161.5 mg, 68%).

¹H NMR [(CD₃)₂SO]: δ8.72 (d, J=8.1 Hz, 2H, H7, H9), 8.45 (s, 1H, H2),7.91 (t, J=7.8 Hz, H8).

4-Chloro-6-nitrobenzothieno[3,2-d]pyrimidine: Dry DMF (5 drops) wasadded to a mixture of 6-nitrobenzothieno[3,2-d]pyrimidone (161 mg, 0.65mmol) and oxalyl chloride (0.28 mL, 3.2 mmol) in 1,2-dichloroethane (5mL). The reaction was heated at 85° C. for 7.5 hours then cooled to 25°C. The solid was Buchner filtered and washed with CH₂Cl₂ and air dried.4-Chloro-6-nitrobenzothieno[3,2-d]pyrimidine was obtained as a graysolid (166 mg, 96% crude).

¹H NMR [(CD₃)₂SO]: δ9.33 (s, 1H, H2), 8.99 (dd, J=7.9, 1.3 Hz, 1H, H7),8.87 (dd, J=8.1, 1.0 Hz, 1H, H9), 8.03 (t, J=7.8 Hz, 1H, H8).

4-([3-Bromophenyl]amino)-6-nitrobenzothieno [3,2-d]pyrimidine: A mixtureof 4-chloro-6-nitrobenzothienopyrimidine (166 mg, 0.62 mmol),m-bromoaniline (0.08 mL, 0.73 mmol) and m-bromoaniline hydrochloride(144 mg, 0.69 mmol) in isopropanol (4.5 mL) was heated at 85° C.stirring under N₂ for 7.5 hours. The dark brown solid was collected byBuchner filtration and washed with isopropanol and air dried to give4-([3-bromophenyl]amino)-6-nitrobenzothieno[3,2-d]pyrimidine (145 mg,67%), mp 247.0-248.1° C.

¹H NMR [(CD₃)₂SO]: δ10.21 (s, 1H, NH), 8.89 (s, 1H, H2), 8.84 (dd,J=7.6, 1.1 Hz, 1H, H7), 8.75 (dd, J=8.0, 0.9 Hz, 1H, H9), 8.25 (s, 1H,H2′), 7.92 (t, J=7.8 Hz, 1H, H8), 7.89 (d, J=6.6 Hz, 1H, H4′), 7.39-7.31(m, 2H, H5′, H6′).

MS (APCI): 403 (100, ⁸¹Br, MH⁺), 402 (17.45, ⁸¹Br, M⁺), 401 (93.01,⁷⁹Br, MH⁺). p Calculated for C₁₆H₉BrN₄O₂S.HCl: C, 43.90; H, 2.30; N,12.80%. Found: C, 44.00; H, 2.43; N, 12.48%.

6-Amino-4-([3-bromophenyl]amino)benzothieno [3,2-d]pyrimidine: Asolution of 4-([3-bromophenyl]amino)-6-nitrobenzothieno[3,2-d]pyrimidine(160 mg, 0.4 mmol) in methanol (10 mL) was subjected to hydrogenationwith Raney Nickel (0.07 g) at 25° C. for 30 hours. After the reactionwas done, the solvent was removed under reduced pressure to leave a darkbrown solid. Recrystalization from wet methanol afforded6-amino-4-([3-bromophenyl]amino)benzothieno[3,2-d]pyrimidine as a brownsolid (70 mg, 43%), mp 217.6-218.8° C.

¹H NMR [(CD₃)₂SO]: δ9.89 (s, 1H, NH), 8.77 (s, 1H, H2), 8.19 (t, J=1.9Hz, H2′), 7.85 (ddd, J=8.1, 2.9, 1.2 Hz, 1H, H4′), 7.64 (dd, J=7.9, 1.0Hz, 1H, H9), 7.34 (t, J=7.6 Hz, 2H, H8, H5′), 7.28 (td, J=8.1, 1.5 Hz,1H, H6′), 6.95 (dd, J=7.4, 1.0 Hz, 1H, H7), 5.71 (brs, 2H, NH2).

MS (APCI): 373 (100, ⁸¹Br, MH⁺), 372 (19.5, ⁸¹Br, M⁺), 371 (96.87, ⁷⁹Br,MH⁺).

Calculated for C₁₆H₁₁BrN₄S.0.3HCl.0.7 CH₃OH: C, 49.57; H, 3.51; N,13.85%. Found: C, 49.47; H, 3.56; N, 13.84%.

To a solution of6-amino-4-[(3-bromophenyl)amino]-benzothieno-quinazoline (130 mg, 0.35mmol), acrylic acid (0.05 mL, 0.73 mmol), and triethylamine (0.1 mL,0.72 mmol) in DMF (3 mL) stirred under N₂ at 0° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (144 mg,0.75 mmol). The reaction gradually warmed up to 25° C. and was quenchedwith water after 20 hours. The formed yellow solid was collected andpurified by sonication with acetone to give the desired product (40 mg,27%), mp 216.4-217.2° C. ¹H NMR [(CD₃)₂SO]: δ10.64 (s, 1H, NH), 9.84 (s,1H, NH), 8.77 (s, 1H, H2), 8.73 (d, J=1.5 Hz, 1H, H6), 8.31 (d, 1H,J=8.8 Hz, H8), 8.20 (s, 1H, H2′), 7.84 (d, J=8.3 Hz, 1H, H6′), 7.67 (dd,J=8.6, 1.7 Hz, 1H, H9), 7.34 (t, J=7.8 Hz, 1H, H5′), 7.28 (d, J=8.1 Hz,1H, H4′), 6.50 (dd, J=16.9, 10.0 Hz, 1H, ═CH), 6.34 (dd, J=17.1, 1.7 Hz,1H, ═CH₂), 5.83 (dd, J=10, 1.7 Hz, 1H ═CH₂).

Mass Spectrum (APCI): 426.7 (100, ⁸¹BrMH⁺), 425.7 (26.28, ⁸¹BrM⁺), 424.7(92, ⁷⁹BrMH⁺).

Calculated for C₁₉H₁₃N₄BrOS.0.3HCl.0.8H₂O: C, 52.28; H, 3.62; N, 12.26%.Found: C, 52.42; H, 3.49; N, 12.41%.

EXAMPLE 44N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3,2-d]pyrimidin-7-yl]acrylamide7-Nitrobenzo[b]thieno[3,2-d]-3H-pyrimid-4-one

2-Fluoro-4-nitrobenzoic acid: [25] To a solution of sodium dichromate(3.87 g, 13 mmol) in acetic acid (20 mL) was added2-fluoro-4-nitrotoluene (1.55 g, 10 mmol) in portions, followed bydropwise addition of concentrated sulfuric acid (10 g). A strongexotherm was observed (100° C.) and the color changed from orange togreen. The reaction was heated at 90° C. for 1 hour and cooled to 25° C.The reaction mixture was dissolved in water (30 mL) and white crystalsformed upon cooling at 0° C. The white solid was collected by filtrationwashed with cold water and dried to give 2-fluoro-4-nitrobenzoic acid(0.99 g, 53%).

¹H NMR (DMSO-d₆) δ: 8.16 (dd, J=10.0, 2.0 Hz, 1H), 8.10-8.03 (m, 2H).

2-Fluoro-4-nitrobenzamide: To a mixture of 2-fluoro-4-nitrobenzoic acid(0.98 g, 5.3 mmol) and oxalyl chloride (0.48 mL, 5.5 mmol) indichloromethane (25 mL), stirred under nitrogen at 25° C., was added 3drops of dimethyl formamide. Gas evolution! The solid slowly dissolvedup and after 4 hours the volatiles were removed under reduced pressure.Saturated aqueous ammonia (5 mL) was added to the residue and themixture was stirred for 10 minutes. The solid was extracted withchloroform (3×20 mL). The combined organic layer was washed with water,saturated brine, and dried (magnesium sulfate). The solvent was removedunder reduced pressure to give 2-fluoro-4-nitrobenzamide (0.83 g, 85%)as a light yellow solid.

¹H NMR (DMSO-d₆): δ8.15 (dd. J=10.0, 2.2 Hz, 1H), 8.06 (dd, J=8.5, 2.2Hz, 1H), 8.02 (brs, 1H), 7.88 (brs, 1H), 7.81 (dd, J=8.3, 7.0 Hz, 1H).

2-Fluoro-4-nitrobenzonitrile: A mixture of 2-fluoro-4-nitrobenzamide(0.83 g, 4.6 mmol) and phosphorus pentoxide/hexamethyl disiloxane in1,2-dichloroethane (20 mL) was heated under nitrogen at 100° C. for 4hours. Upon cooling, the solution was poured onto a plug of silica geland washed with hexane (200 mL) followed by 5% methanol/chloroform (400mL). The methanol/chloroform washes were collected and concentratedunder reduced pressure to give 2-fluoro-4-nitrobenzonitrile (0.71 g,95%) as a beige solid.

¹H NMR (DMSO-d₆): δ8.46 (dd, J=9.5, 2.0 Hz, 1H), 8.37-8.22 (m, 2H).

Methyl 3-amino-6-nitrobenzothiophene-2-carboxylate: Methylthioglycollate (0.08 mL, 0.85 mmol) was added to a solution of2-fluoro-4-nitrobenzonitrile (145 mg, 0.87 mmol), and triethylamine(0.14 mL, 1.0 mmol) in acetonitrile (20 mL) stirred under nitrogen at25° C. After 3 hours further triethylamine (0.28 mL, 2.0 mmol) was addedto the solution, which was stirred at 25° C. for a further 16 hours. Thesolvent was removed under reduced pressure to give a brown residue,which upon trituration with chloroform precipitated methyl3-amino-6-nitrobenzothiophene-2-carboxylate (103 mg, 54%) as a red brownsolid, mp 228.5-229.5° C.

¹H NMR (DMSO-d₆): δ8.87 (d, J=2.0 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 8.15(dd, J=8.8, 2.0 Hz, 1H), 7.26 (brs, 2H), 3.77 (s, 3H).

Mass Spectrum (CI): 253 (100, MH⁺), 252 (52, M⁺).

7-Nitrobenzo[b]thieno[3,2-d]-3H-pyrimid-4-one: A mixture of methyl3-amino-6-nitrobenzothiophene-2-carboxylate (20 mg, 0.08 mmol) andformamidine acetate (59 mg, 0.57 mmol) was heated at 190° C. for 5 hoursand cooled to 25° C. The reaction residue was triturated with water, and7-nitrobenzo[b]thieno[3,2-d]-3H-pyrimid-4-one (7 mg, 36%) was obtainedby Buchner filtration as a dark brown solid, mp >320° C.

¹H NMR (DMSO-d₆): δ9.21 (d, J=1.7 Hz, 1H), 8.39 (d, J=8.5 Hz, 1H), 8.38(s, 1H), 8.32 (dd, J=8.8, 2.0 Hz, 1H).

Mass Spectrum (CI): 248 (100, MH⁺), 247 (30, M⁺).

Analysis calculated for C₁₀H₅N₃O₃S: C, 48.58; H, 2.04; N, 17.00%. Found:C, 48.19; H, 2.09; N, 16.77%.

To a solution of 7-amino-4-[(3-bromophenyl)amino]benzothieno-pyrimidine(88 mg, 0.24 mmol), acrylic acid (0.03 mL, 0.44 mmol), and triethylamine(0.09 mL, 0.64 mmol) in DMF (3 mL), stirred under nitrogen at 0° C., wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84mg, 0.44 mmol). The reaction gradually warmed up to 25° C. and wasquenched with water after 24 hours. The light brown precipitate wascollected and purified by sonication with acetone. The desired productwas isolated as a beige solid (59 mg, 37%), mp 251.0-252.4° C.

¹H NMR [(CD₃)₂SO]: δ10.58 (s, 1H, NH), 9.92 (s, 1H, NH), 8.84 (s, 1H,H2), 8.28-8.24 (m, 2H, H6, H2′), 7.88 (d, 1H, J=6.8 Hz, H6′), 7.70 (dd,J=7.6, 1.2 Hz, 1H, H8), 7.65 (t, J=7.6 Hz, 1H, H9), 7.33 (t, J=8.0 Hz,1H, H5′), 7.28 (dd, J=6.9, 1.8 Hz, 1H, H4′), 6.60 (dd, J=16.8, 10.0 Hz,1H, ═CH), 6.36 (dd, J=17.1, 1.9 Hz, 1H, ═CH2), 5.88 (dd, J=10.3, 1.7 Hz,1H, ═CH₂).

Mass Spectrum (APCI): 426.7 (100, MH⁺), 425.7 (18.68, M⁺). Calculatedfor C₁₉H₁₃N₄BrOS.H₂O: C, 51.47; H, 3.41; N, 12.64%. Found: C, 51.42; H,3.39; N, 12.40%.

EXAMPLE 45 N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]buta-2,3-dienamide

To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg,1.0 mmol), and 3-butynoic acid (173 mg, 2.06 mmol) in DMF (5 mL) stirredunder nitrogen at 0° C. was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (384 mg, 2.0mmol). After 1.5 hours the reaction was quenched with 0.1 M HCl solution(10 mL). The yellow precipitate was collected by Buchner filtration andwashed with water followed by acetone. The solid was taken up intoacetone with the addition of triethylamine. The formed solution wasfiltered through a 2-inch silica gel eluting with 50% acetone/CH₂Cl₂.The filtrate was collected and concentrated under reduced pressure togive the title compound as a yellow solid (247 mg, 56%), mp 268-270° C.

¹H NMR [(CD₃)₂SO]: δ10.39 (s, 1H, NH), 9.93 (s, 1H, NH), 8.76 (d, J=2.2Hz, 1H, H5), 8.58 (s, 1H, H2), 8.18 (s, 1H, H2′), 7.87 (dt, J=9.0, 1.9Hz, 2H, H7, H8), 7.79 (d, J=8.8 Hz, 1H, H6′), 7.34 (t, J=7.9 Hz, 1H,H5′), 7.29 (d, J=8.3 Hz, 1H, H4,), 6.07 (t, J=6.5 Hz, 1H, CH═C═CH₂),5.49 (d, J=6.6 Hz, 2H, ═C═CH₂).

Mass Spectrum (APCI): 382.8 (88, ⁸¹BrMH⁺), 381.8 (19, ⁸¹BrM⁺), 380.7(100, ⁷⁹BrMH⁺).

Calculated for C₁₈H₁₃N₄BrO.0.08H₂O.0.8C₃H₆O: C, 55.42; H, 4.42; N,12.68%. Found: C, 55.13; H, 4.17; N, 12.87%.

EXAMPLE 46N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E,4-oxopent-2-enamide

6-Amino-4-[(3-bromophenyl)amino]quinazoline (0.23 g, 0.75 mmol) andN-ethyl diisopropylamine (0.26 mL, 1.5 mmol) were added to a solution ofE,4-oxopent-2-enoic acid (171 mg, 1.5 mmol) and EDAC.HCl (288 mg, 1.5mmol) in THF/DMF (3:1, 4 mL) stirred under N₂ at 25° C. The ice bath wasremoved, and the reaction mixture was stirred at 25° C. for 4 hours,when further N-ethyl diisopropylamine (0.13 mL, 0.75 mmol),E,4-oxopent-2-enoic acid (86 mg, 0.75 mmol) and EDAC.HCl (144 mg, 0.75mmol) were added. After stirring a further 14 hours at 25° C., thereaction mixture was added dropwise to stirred cold water (100 mL). Thesolid was collected, dissolved in MeOH (50 mL) and dried onto silica gel(3 g). This was used as the origin in a silica gel flash column (80 g)eluting with 10% MeOH/CH₂Cl₂. Concentration of pure fractions underreduced pressure gaveN-[4-[(3-bromophenyl)amino]quinazolin-6-yl]-E,4-oxopent-2-enamide (0.14g, 45%) as a yellow solid, mp 230° C. (decomp.).

¹H NMR [(CD₃)₂SO]: δ10.91 (s, 1H, NH), 9.99 (s, 1H, NH), 8.87 (d, J=1.9Hz, 1H, H5), 8.60 (s, 1H, H2), 8.17 (t, J=1.9 Hz, 1H, H2′), 7.85 (m, 3H,H7, H8, H6′), 7.37 (m, 2H, H5′, H4′), 7.15 (d, J=15.7 Hz, 1H,H3-pentenyl), 6.99 (d, J=15.7 Hz, 1H, H2-pentenyl), 2.40 (s, 3H, Me).

Mass Spectrum (APCI): 412.7 (100, ⁸¹BrMH⁺), 410.8 (98, ⁷⁹BrMH⁺).

Calculated for C₁₉H₁₅BrN₄O₂: C, 55.49; H, 3.68; N, 13.62%. Found: C,55.21; H, 3.72; N, 13.35%.

EXAMPLE 47N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E,4-ethoxy-4-oxobut-2-enamide

6-Amino-4-[(3-bromophenyl)amino]quinazoline (0.23 g, 0.75 mmol) andN-ethyl diisopropylamine (0.26 mL, 1.5 mmol) were added to a solution ofE,4-ethoxy-4-oxobut-2-enoic acid (216 mg, 1.5 mmol) and EDAC.HCl (288mg, 1.5 mmol) in THF/DMF (3:1, 4 mL) stirred under N₂ at 25° C. The icebath was removed, and the reaction mixture was stirred at 25° C. for 4hours, when further N-ethyl diisopropylamine (0.13 mL, 0.75 mmol),E,4-ethoxy-4-oxobut-2-enoic acid (108 mg, 0.75 mmol), and EDAC.HCl (144mg, 0.75 mmol) were added. After stirring a further 14 hours at 25° C.,the reaction mixture was added dropwise to stirred cold water (100 mL).The solid was collected, dissolved in MeOH (50 mL), and dried ontosilica gel (3 g). This was used as the origin in a silica gel flashcolumn (80 g) eluting with 10% MeOH/CH₂Cl₂. Concentration of purefractions under reduced pressure gaveN-[4-((3-bromophenyl)amino]quinazolin-6-yl)-E,4-ethoxy-4-oxobut-2-enamide(0.19 g, 58%) as a yellow solid, mp >255° C.

¹H NMR [(CD₃)₂SO]: δ10.93 (s, 1H, NH), 9.99 (s, 1H, NH), 8.89 (d, J=1.9Hz, 1H, H5), 8.60 (s, 1H, H2), 8.16 (t, J=1.9 Hz, 1H, H2′), 7.85 (m, 3H,H7, H8, H6′), 7.33 (m, 3H, H5′,H4′, H3-pentenyl), 6.79 (d, J=15.4 Hz,1H, H2-pentenyl), 4.24 (q, J=7.1 Hz, CH₂), 1.29 (t, J=7.1 Hz, 3H, Me).

Mass Spectrum (APCI): 442.8 (99, ⁸¹BrMH⁺), 440.8 (100, ⁷⁹BrMH⁺).

Calculated for C₂₀H₁₇BrN₄O₃: C, 54.44; H, 3.88; N, 12.70%. Found: C,54.59; H, 3.83; N, 12.67%.

EXAMPLE 48N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]penta-2,4-dienamide

To a 0-5° C. solution of6-amino-4-[(3-bromophenyl)-amino]pyrido[3,4-d]pyrimidine (160 mg, 0.5mmol), 80% trans-2,4-pentadienoic acid (245 mg, 2 mmol), and pyridine,(0.5 mL) in 2:1 THF:DMA (3 mL) stirred under N₂ was added in one portion1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (490 mg, 2.5mmol). Cooling was removed, and the viscous mixture was stirred at 25°C. After 23 hours, the mixture was charged with additionaltrans-2,4-pentadienoic acid (125 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (240 mg),and 2:1 THF:DMA (2 mL). After stirring for another 19 hours, the mixturewas diluted with water and ethyl acetate. The biphasic mixture waswarmed, then filtered through celite with the filter pad washed wellwith water and hot ethyl acetate. The filtrate was extracted with ethylacetate (3×), and the combined organic phases were washed with brine,dried (MgSO₄), and concentrated to a solid. The solid was dissolved inhot ethyl acetate and the solution purified by column chromatographyover flash SiO₂ eluting with ethyl acetate. Product fractions werepooled and concentrated to a solid that was triturated in warm ethylacetate. After cooling, the solids were collected and dried to leave theproduct (27 mg, 13%), mp 210-215° C.

¹H NMR [(CD₃)₂SO]: δ11.04 (s, 1H, exchanges D₂O), 10.34 (s, 1H,exchanges D₂O), 9.04 (s, 1H), 9.02 (s, 1H), 8.66 (s, 1H), 8.17 (t, J=1.9Hz, 1H), 7.89 (dt, J=7.7, 1.7 Hz, 1H), 7.40-7.27 (m, 3H), 6.60 (dt,J=16.9, 10.6 Hz, 1H), 6.53 (d, J=15.2 Hz, 1H), 5.75 (d, J=16.9 Hz, 1H),5.56 (d, J=11.1 Hz, 1H).

Mass Spectrum (APCI) m/z (relative %): 395.9 (89), 396.9 (20), 397.9(100), 398.9 (20).

Analysis calculated for C₁₈H₁₄N₅OBr.0.3 H₂O.0.2 C₄H₈O₂: C, 53.86; H,3.89; N, 16.70. Found: C, 54.02; H, 3.77; N, 16.33.

EXAMPLE 49N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-(2-(N,N-dimethylamino)ethyl)acrylamide

To a 0-5° C. solution of4-[3-bromophenyl)amino]-6-(2-dimethylaminoethyl)aminopyrido[3,4-d]pyrimidine(387 mg, 1 mmol) and redistilled acrylic acid (0.25 mL, 3.6 mmol) inpyridine (5 mL) stirred under N₂ was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg, 5mmol). After 30 minutes, cooling was removed, and the solution wasstirred for an additional 45 minutes. The solution was diluted with 1%aqueous sodium bicarbonate and extracted with ethyl acetate (4×). Thecombined extracts were washed with brine, dried (MgSO₄), andconcentrated to leave an oil that was crystallized from ethyl acetate at5° C. overnight to leave product (122 mg, 28%), mp >160° C. (dec).

¹H NMR [(CD₃)₂SO]: 10.16 (s, 1H, exchanges D₂O), 9.15 (s, 1H), 8.80 (s,1H), 8.43(s, 1H), 8.22 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.42-7.35 (m,2H), 6.29-6.22 (m, 2H), 5.66 (dd, J=9.0, 3.5 Hz, 1 H), 4.05 (t, J=7.1Hz, 2H) 2.42 (t, J=7.1 Hz, 2H), 2.11 (s, 6H).

Mass Spectrum (APCI) m/z (relative %): 440.9 (99), 441.8 (23), 442.8(100), 443.9 (24).

Analysis calculated for C₂₀H₂₁N₆OBr: C, 54.43; H, 4.80; N, 19.04. Found:C, 54.15; H, 4.65; N, 18.76.

EXAMPLE 50N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]E-but-2-enamide

To a 0-5° C. solution of6-amino-4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine (32 mg, 0.1mmol), transcrotonic acid (35 mg, 0.4 mmol), in pyridine (0.4 mL)stirred under N₂ was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (98 mg, 0.5 mmol). Cooling was removed and the mixture wasstirred at 25° C. After 2 hours, the solution was diluted with water,and the suspension was stirred for 15 minutes. The solids werecollected, then dissolved in ethyl acetate. The solution was washed with5% aqueous sodium bicarbonate, dried (MgSO₄), and filtered through flashSiO₂. The filtrate was concentrated to a solid that was triturated inhot ethyl acetate. The solids were collected to leave product, (11 mg,28%) mp >260° C. (dec).

¹H NMR [(CD₃)₂SO]: δ10.87 (s, 1H, exchanges D₂O), 10.31 (s, 1H,exchanges D₂O), 9.03 (s, 1H), 9.00 (s, 1H), 8.65 (s, 1H), 8.17 (s,1H),7.89 (d, J=7.5 Hz, 1H), 7.39-7.33 (m, 2H), 6.99-6.90 (m, 1H), 6.39 (dd,J=15.4, 1.7 Hz, 1H), 1.91 (dd, J=7.0, 1.4 Hz, 3H.

Mass Spectrum (APCI) m/z (relative %): 381.8 (74), 382.8 (27), 383.8(100), 384.8 (30), 385.9 (10).

Analysis calculated for C₁₇H₁₄N₅OBr.0.3 H₂O: C, 52.40; H, 3.78; N,17.97. Found: C, 52.37; H, 3.65; N, 17.70.

EXAMPLE 51N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]cinnamide

To a 0-5° C. solution of6-amino-4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine (32 mg, 0.1mmol), transcinnamic acid (60 mg, 0.4 mmol), in pyridine (0.4 mL)stirred under N₂ was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (98 mg, 0.5 mmol). Cooling was removed, and the mixturewas stirred at 25° C. After 2 hours, the solution was diluted withwater, and the suspension was stirred for 15 minutes. The solids werecollected, then dissolved in ethyl acetate. The solution was washed with5% aqueous sodium bicarbonate, dried (MgSO₄), and filtered through flashSiO₂. The filtrate was concentrated to a solid that was triturated inhot ethyl acetate. The solids were collected to leave product, (23 mg,51%) mp 253-256° C.

¹H NMR [(CD₃)₂SO]: δ11.07 (s, 1H, exchanges D₂O), 10.36 (s, 1H,exchanges D₂O), 9.06 (s, 2H; with D₂O wash, collapses to 9.06 [s, 1H]and 9.02 [s, 1H]), 8.67 (s, 1H), 8.19 (s, 1H), 7.90 (d, J=7.7 Hz, 1H),7.72-7.65 (m, 3H), 7.51-7.34 (m, 5H), 7.14 (d, J=15.7, 1H).

Mass Spectrum (APCI) m/z (relative %): 445.9 (97), 446.9 (24), 447.9(100), 448.9 (26).

Analysis calculated for C₂₂H₁₆N₅OBr.0.2 H₂O: C, 58.73; H, 3.67; N,15.57. Found: C, 58.79; H, 3.66; N, 15.37.

EXAMPLE 52N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-E,3-chloroacrylamide

To a −20° C. solution of6-amino-4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine (128 mg, 0.4mmol), and cis-3-chloroacrylic acid acid (172 mg, 1.6 mmol) in pyridine(2 mL) stirred under N₂ was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (392 mg, 1.5mmol). After 4.5 hours, additional cis-3-chloroacrylic acid acid (57 mg)and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg)were added and the temperature was brought to −10° C. After a totalreaction time of 7 hours, the viscous, dark mixture was diluted with DMFand the resultant solution was poured into 1:1 ethyl acetate:water. Theresultant mixture was shaken vigorously and the phases separated. Theaqueous phase was further extracted (2×), then the combined organicphases were washed with brine (2×), dried (MgSO₄), and filtered throughflash SiO₂. The filtrate was concentrated to a solid that was dissolvedin warm ethyl acetate. The solution was purified by columnchromatography over flash SiO₂ eluting with ethyl acetate. The productfractions were pooled and concentrated to solid that was triturated in1:1 ethyl acetate:tert-butyl methyl ether. The solids were collected anddried at 0.1 mm/25° C. to leave product (30 mg, 18%) of product, mp165-175° C. (dec) following crystallization from ethyl acetate.

¹H NMR [(CD₃)₂SO]: δ11.09 (s, 1H, exchanges D₂O), 10.38 (s, 1H,exchanges D₂O), 9.04 (s, 1H), 9.00 (s, 1H), 8.66 (s, 1H), 8.16 (t, J=1.9Hz, 1H), 7.88 (dt, J=7.7, 1.7 Hz, 1H), 7.40-7.33 (m, 2H), 7.07 (d, J=8.0Hz, 1H), 6.77 (d, J=8.0 Hz, 1H).

Mass Spectrum (APCI) m/z (relative %): 365.8 (29), 366.8 (36), 367.8(35), 368.8 (35), 401.8 (82), 402.8 (18), 403.8 (100), 404.8 (20), 405.8(29).

Analysis calculated for C₁₆H₁₁N₅OBrCl.0.2 H₂O.0.2 C₄H₈O₂: C, 47.38; H,3.08; N, 16.44. Found: C, 47.53; H, 3.15; N, 16.25.

EXAMPLE 53N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-propynamide

To a −20° C. solution of6-amino-4-[(3-bromophenyl)amino]pyrido[3,4-d]pyrimidine (94 mg, 0.3mmol), and propiolic acid (66 μL, 1.05 mmol) in pyridine (1.2 mL)stirred under N₂ was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (294 mg, 1.5 mmol). After 2.25 hours, additional propiolicacid (33 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (147 mg) were added to the cold solution. After a totalreaction time of 7.5 hours, the viscous, dark mixture was diluted withDMF, and the resultant solution was poured into 1:1 ethyl acetate:water.The resultant mixture was shaken vigorously and the phases separated.The aqueous phase was further extracted (2×), then the combined organicphases were washed with brine (2×), dried (MgSO₄), and filtered throughflash SiO₂. The filtrate was concentrated to a solid that was dissolvedin warm ethyl acetate. The solution was purified by columnchromatography over flash SiO₂ eluting with ethyl acetate. The productfractions were pooled and concentrated to solid that was triturated in1:1 ethyl acetate:tert-butyl methyl ether. The solids were collected anddried at 0.1 nm/25° C. to leave product (16 mg, 14%), mp >150° C. (dec).

¹H NMR [(CD₃)₂SO]: δ11.69 (s, 1H, exchanges D₂O), 10.31 (s, 1H,exchanges D₂O), 9.05 (s, 1H), 8.83 (s, 1H), 8.68 (s, 1H), 8.15 (s, 1H),7.87 (d, J=7.2 Hz, 1H), 7.40-7.33 (m, 2H), 4.54 (s, 1H).

Mass Spectrum (APCI) m/z (relative %): 365.8 (69), 366.8 (28), 367.8(100), 368.9 (50), 369.9 (14).

Analysis calculated for C₁₆H₁₀N₅OBr.0.1 H₂O.0.1 C₄H₈O₂: C, 52.00; H,2.93; N, 18.49. Found: C, 51.89; H, 2.78; N, 18.50.

EXAMPLE 54N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E,4-(3-(N,N-dimethylamino)propoxy-4-oxobut-2-enamidetris trifluoroacetate

A solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (158 mg, 0.5mmol) in THF (10 mL) was added dropwise over 15 minutes to a solution offumaroyl chloride (382 mg, 2.5 mmol) in THF (10 mL) stirred under N₂ at0° C. After 1 hour at 0° C., the suspension was allowed to settle, andthe supernatant was decanted. Fresh THF (5 mL) was added, and thesuspension was stirred at 0° C. whilst a solution of3-(N,N-dimethylamino)propan-1-ol (1.18 mL, 10 mmol) in THF (5 mL) wasadded dropwise. The suspension was stirred at 25° C. for 1 hour, thesolvent was stripped under reduced pressure, and the residue was treatedwith cold water. The solid was collected by Buchner filtration,dissolved in a minimum DMF, and absorbed onto silica gel (2 g) anddried. The solid was used as the origin in silica gel flashchromatography (50 g) eluting with CH₂Cl₂/MeOH (2:1). The best fractionswere pooled, and stripped, dissolved in acetic acid/water (3:2, 2.5 mL),passed through a 0.45μ filter, and purified by HPLC on a Vidac C18218TP1022 reverse phase HPLC column, eluting with a 10% to 50% gradientof 0.1% TFA in water/0.1% TFA in CH₃CN over 60 minutes. The purefractions were pooled and lyophilized to giveN-[4-[(3-bromophenyl)amino]-quinazolin-6-yl]-E,4-(3-(N,N-dimethylamino)propoxy-4-oxobut-2-enamidetris trifluoroacetate (51 mg, 12%) as a yellow solid, mp 60° C.

¹H NMR [(CD₃)₂SO]: δ11.14 (s, 1H, NH), 10.85 (br s, 1H, NH), 9.57 (br s,1H, NH), 9.01 (d, J=1.7 Hz, 1H, H5), 8.79 (s, 1H, H2), 8.07 (s, 1H,H2′), 8.02 (dd, J=2.1, 9.0 Hz, 1H, H7), 7.89 (d, J=8.9 Hz, 1H, H8), 7.78(d, J=6.5 Hz, H6′), 7.43 (m, 2H, H4′& H5′), 7.34 (d, J=15.4 Hz, 1H,H3-butenyl), 6.84 (d, J=15.4 Hz, 1H, H2-butenyl), 4.26 (t, J=6.2 Hz, 2H,OCH₂), 3.19 (m, 2H, CH₂N), 2.81 (d, J=4.6 Hz, 6H, Me), 2.05 (m, 2H,CH₂).

Mass Spectrum (APCI): 499.8 (100, ⁸¹BrMH⁺), 497.9 (97, ⁷⁹BrMH⁺).

Calculated for C₂₃H₂₄BrN₅O₃. 3CF₃COOH: C, 40.15; H, 3.49; N, 8.07%.Found: C, 40.06; H, 3.36; N, 8.25%.

EXAMPLE 55 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylicacid (Z)

To a solution of 6-amino-4-[(3-bromophenyl)amino]-quinazoline (0.78 g,2.5 mmol) in 8 mL of DMF was added maleic anhydride (0.266 g, 2.7 mmol),and the mixture was heated with stirring in a 70° C. oil bath for 2.5hours. The resulting suspension was cooled to room temperature and thendiluted with water. The solid was collected, washed sequentially with amixture of toluene/DMF (1:1), water, and IPA. The solid was dried invacuo at 60° C. for 16 hours to afford3-[4-(3-bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid (Z)(0.87 g, 86%) as a pale yellow powder, mp 224-225° C. (decompositionwith gas evolution).

¹H NMR [(CD₃)₂SO]: δ13.00 (br s, 1H, COOH), 10.85 (br s, 1H, NH), 9.96(br s, 1H, NH), 8.73 (d, J=1.8 Hz, 1H, H5), 8.54 (s, 1H, H2), 8.11 (brs, 1H, Me₂NCHO), 7.91-7.75 (m, 4H), 7.32-7.24 (m, 2H), 6.46 (d, J=12.0Hz, 1H, CH═CH), 6.35 (d, J=12.0 Hz, 1H, CH═CH), 2.84 (s, 3H, Me ₂NCHO),2.68 (s, 3H, Me ₂NCHO). Mass Spectrum (APCI): 412.8 (100, ⁸¹BrM⁺), 410.8(96, ⁷⁹BrM⁺); 413.8 (26, ⁸¹BrMH⁺), 411.8 (24, ⁷⁹BrMH⁺).

Calculated for C₁₈H₁₃BrN₄O₃.0.81 DMF: C, 51.94; H, 3.98; N, 14.26%.Found: C, 51.97; H, 3.98; N, 14.40%.

EXAMPLE 56N-[4-[(3-Bromophenyl)amino]quinazolin-6-yl]-E,4-(3-(N,N-dimethylamino)propylamino-4-oxobut-2-enamide

A solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (158 mg, 0.5mmol) in THF (10 mL) was added dropwise over 15 minutes to a solution offumaroyl chloride (382 mg, 2.5 mmol) in THF (10 mL) stirred under N₂ at0° C. After 1 hour at 0° C., the suspension was allowed to settle, andthe supernatant was decanted. Fresh THF (5 mL) was added and thesuspension was stirred at 0° C. whilst a solution of3-(N,N-dimethylamino)prop-1-ylamine (1.26 mL, 10 mmol) in THF (5 mL) wasadded dropwise. The suspension was stirred at 25° C. for 1 hour, thesolvent was stripped under reduced pressure, and the residue was treatedwith cold water. The solid was collected by Buchner filtration,dissolved in boiling MeOH (25 mL), filtered, and the solvent was removedunder reduced pressure. The residue was dissolved in acetic acid/water(3:2, 2.5 mL), and purified by HPLC on a Vidac C18 218TP1022 reversephase HPLC column, eluting with a 10% to 50% gradient of 0.1% TFA inwater/0.1% TFA in CH₃CN over 60 minutes. The pure fractions were pooledand lyophilized to giveN-[4-[(3-bromophenyl)-amino]quinazolin-6-yl]-E,4-(3-(N,N-dimethylamino)prop-1-ylamino-4-oxobut-2-enamidetris trifluoroacetate (154 mg, 37%) as a yellow solid, mp 40° C.

¹H NMR [(CD₃)₂SO]: δ11.02 (s, 1H, NH), 9.50 (br s, 1H, NH), 9.02 (d,J=1.7 Hz, 1H, H5), 8.82 (s, 1H, H2), 8.74 (t, J=5.7 Hz, 1H, NH), 8.05(s, 1H, H2′), 8.02 (dd, J=2.1, 9.0 Hz, 1H, H7), 7.89 (d, J=8.9 Hz, 1H,H8), 7.76 (d, J=7.2 Hz, H6′), 7.45 (m, 2H, H4′& H5′), 7.17 (d, J=14.9Hz, 1H, H3-butenyl), 7.05 (d, J=15.2 Hz, 1H, H2-butenyl), 3.26 (m, 2H,NCH₂), 3.08 (m, 2H, CH₂N), 2.79 (d, J=4.8 Hz, 6H, Me), 1.83 (m, 2H,CH₂).

Mass Spectrum (APCI): 498.8 (100, ⁸¹BrMH⁺), 496.9 (97, ⁷⁹BrMH⁺).

Calculated for C₂₃H₂₅BrN₆O₂. 3CF₃COOH: C, 41.49; H, 3.36; N, 10.01%.Found: C, 41.44; H, 3.60; N, 10.33%.

EXAMPLE 574-[(3-Bromo-phenyl)amino]-6-(ethenesulfonyl)pyrido-[3,4-d]pyrimidine;2-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylsulfanyl]-ethanol

A nitrogen purged solution of 2-mercaptoethanol (1.75 mL, 25 mmol), and4-[3-bromophenyl)amino]-6-fluoropyrido[3,4-d]pyrimidine (1.6 g, 5 mmol),in DMSO (10 mL) was treated with anhydrous cesium carbonate (3.26 g, 10mmol). The stirred solution was heated at 50° C. for 2 hours, thenpoured into 2% aqueous hydrochloric acid (180 mL). After stirring thesuspension for 15 minutes, the solids were collected, washed well withwater, and dissolved in DMF. The solution was poured into 1:1water:ethyl acetate and the resultant mixture was extracted with ethylacetate (3×). The combined extracts were washed with brine, dried(MgSO₄), and filtered through flash SiO₂. The filtrate was concentratedto a solid that was triturated in ethyl acetate. The solids werecollected to give 1.24 g (66%) the product, mp 182-185° C. in two crops,and 98 mg (5%) of a third crop, mp 179-183° C.

¹H NMR [(CD₃)₂SO]: δ10.03 (s, 1H, exchanges D₂O), 9.10 (s, 1H), 8.69 (s,1H), 8.35 (s, 1H), 8.22 (t, J=1.9 Hz, 1H), 7.91 (dt, J=7.7, 1.9 Hz, 1H),7.42-7.34 (m, 2H), 5.04 (t, J=5.5 Hz, exchanges D₂O, 1H), 3.68 (dd,J=6.8, 5.7 Hz, 2H), 3.36 (t, J=6.8 Hz, 2H).

Mass Spectrum (APCI) m/z (relative %): 374.8 (49), 375.8 (10), 376.9(100), 377.8 (23), 378.9 (63), 379.8 (14).

Analysis calculated for C₁₅H₁₃N₄OSBr: C, 47.76; H, 3.47; N, 14.85.Found: C, 47.65; H, 3.38; N, 14.55.

2-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidine-6-sulfonyl]-ethanol

A 0-5° C. stirred suspension of2-[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylsulfanyl]-ethanol(755 mg, 2 mmol) in chloroform (30 mL) was treated withmeta-chloroperbenzoic acid (1.27 g, 57-86%). The suspension was slowlywarmed to 25° C. over a 4 hour period. After 14.5 and 17.5 hours,respectively, the suspension was treated with an additional charge ofthe oxidant (720 mg, 720 mg). After 19.5 hours total reaction time, thethin suspension was cooled to 0-5° C., and treated with DMSO (2 mL).Cooling was removed, and the solution was stirred for 30 minutes. Themixture was then distributed between ethyl acetate and 5% aqueous sodiumbicarbonate. The organic phase was washed with brine, dried (MgSO₄), andconcentrated to a reduced volume that was purified by flash SiO₂ columnchromatography eluting with ethyl acetate. The product fractions werecombined and concentrated to a solid that was crystallized from ethylacetate to give the product (460 mg, 56%), mp 210-212° C. The filtratewas further processed to afford 84 mg (10%) of a second crop, mp208-209° C.

¹H NMR (CF₃CO₂H): δ10.96 (s, 1H), 10.90 (s, 1H), 10.42 (s, 1H), 9.47 (s,1H), 9.16 (d, J=8.2 Hz, 1H), 9.05 (d, J=8.2 Hz, 1H), 8.83 (t, J=8.0,1H), 5.81 (t, J=5.2 Hz, 2 H), 5.43 (t, J=5.2 Hz, 2 H).

Mass Spectrum (APCI) m/z (relative %): 378.7 (39), 380.7 (45), 408.7(100), 409.7 (15), 410.7 (97), 411.7 (17).

Analysis calculated for C₁₅H₁₃N₄O₃SBr: C, 44.02; H, 3.20; N, 13.69.Found: C, 44.09; H, 3.14; N, 13.44.

4-[(3-Bromo-phenyl)amino]-6-(ethenesulfonyl)pyrido-[3,4-d]pyrimidine

To a 0-5° C. stirred suspension of2-[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidine-6-sulfonyl]-ethanol(41 mg, 0.1 mmol), and triethylamine (31 μL, 0.22 mmol) indichloromethane (0.5 mL) under N₂ was added dropwise methanesulfonylchloride (9.3 μL, 0.12 mmol). Additional charges of methanesulfonylchloride (9.3 μL, 9.3 μL) were added after 45 minutes, and 1.5 hours,the latter with additional triethylamine (50 μL). After reaction for atotal of 2.5 hours, the cold solution was quenched with 5% aqueoussodium bicarbonate, then extracted with ethyl acetate (2×). The combinedorganic extracts were dried (MgSO₄) then filtered through a pad of flashSiO₂. The filtrate was concentrated to a solid that was crystallizedfrom ethyl acetate to leave the product (17 mg, 44%), Mp 214-217° C.

¹H NMR [(CD₃)₂SO]: δ10.64 (s, 1H, exchanges D₂O), 9.30 (s, 1H), 9.25 (s,1H), 8.87 (s, 1H), 8.16 (s, 1H), 7.89-7.85 (m, 1H), 7.39-7.33 (m, 2H),7.17 (dd, J=10.0, 16.5 Hz, 1H), 6.46 (d, J=16.4 Hz, 1H), 6.37 (d, J=10.0Hz, 1H).

EXAMPLE 58N-(3-Bromo-phenyl)-N-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-quinazolin-4-yl]-acetamide

Sodium acetate (0.10 g, 1.2 mmol) was added to a suspension of3-[4-(3-bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid (Z)(0.25 g, 0.61 mmol) in 5 mL of acetic anhydride, and the mixture washeated under reflux for 30 minutes. After cooling to room temperature,the reaction was filterd and the filtrate concentrated to dryness invacuo. The residue was taken up in EtOAc and washed sequentially withsaturated sodium bicarbonate, water, and brine. The EtOAc portion wasdried over magnesium sulfate, filtered and concentrated to afford afaintly pink solid. The solid was recrystallized twice from EtOAc toaffordN-(3-bromo-phenyl)-N-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-quinazolin-4-yl]-acetamide(0.104 g, 39%) as an off-white powder, mp 174-175° C.

¹H NMR [CDCl₃]: δ9.24 (s, 1H, H2), 8.16 (d, J=9 Hz, 1H, H8), 8.10 (d,J=2 Hz, 1H, H5), 8.03 (dd, J=9 Hz, J=2 Hz, 1H, H7), 7.59 (t, 1H, J=2 Hz,H2′), 7.45 (m, 1H, H4′), 7.38 (m, 1H, H6′), 7.27 (d, 1H, J=7 Hz, H5′),6.91 (s, 2H, CH═CH), 2.15 (s, 3H, CH₃).

Mass Spectrum (APCI): 438.7 (89, ⁸¹BrMH⁺), 436.7 (79, ⁷⁹BrMH⁺); 439.7(17, ⁸¹BrM⁺), 437.7 (19, ⁷⁹BrM⁺); 470.7 (100, ⁸¹BrM⁺MeOH), 468.8 (95,⁷⁹BrM⁺MeOH).

Calculated for C₂₀H₁₃BrN₄O₃: C, 54.94; H, 3.00; N, 12.81%. Found: C,54.90; H, 2.97; N, 12.61%.

The following compounds can be made using the schemes and examplesprovided above:

1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-pyrrole-2,5-dione;

1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-prop-2-en-1-one;

Acrylic acid 4-(3-bromo-phenylamino)-quinazolin-6-yl ester;

MethylN-[4-[(3-bromophenyl)amino]-P-ethenyl-pyrido[3,4-d]pyrimidin-6-yl]phosphonamidate;

Acrylic acid 4-(3-bromo-phenylamino)-quinazolin-7-yl ester;

1-[4-(3-Bromo-phenylamino)-quinazolin-6-yl]-but-3-en-2-one;

Acrylic acid 4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-ylester;

N-[4-(3-Bromo-phenylamino)-7-(3-morpholin-4-yl-propoxy)-pyrido[3,2-d]pyrimidin-6-yl]-acrylamide;

Penta-2,3-dienoic acid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

Propa-1,2-diene-1-sulfonicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

MethylN-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-P-(1,2-propadienyl)phosphonamidate;

N-[1-(3-Bromo-phenylamino)-9H-2,4,9-triaza-fluoren-7-yl]-acrylamide;

N-[4-(3-Bromo-phenylamino)-9H-1,3,9-triaza-fluoren-6-yl]-acrylamide;

N-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-acrylamide;

N-(4-Phenylmethylamino-quinazolin-6-yl)-acrylamide;

(S)-N-[4-(1-Phenyl-ethylamino)-quinazolin-6-yl]-acrylamide;

(R)-N-[4-(1-Phenyl-ethylamino)-quinazolin-6-yl]-acrylamide;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide(3-dimethylamino-propyl)-amide;

N-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide;

N-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-methyl-acrylamide;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-dimethylamino-propyl)-amide;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;

4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Dimethylamino-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-(4-Methyl-piperazin-1-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-(4-methyl-piperazin-1-yl)-ethyl ester;

4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-(imidazol-1-yl)-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide];

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];

4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-morpholin-4-yl-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-{[3-4-methyl-piperazin-1-yl)-propyl]-amide};

(3-Chloro-4-fluoro-phenyl)-{6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;

(3-Chloro-4-fluoro-phenyl)-(6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(3-Chloro-4-fluoro-phenyl)-[6-(5-morpholin-4-yl-pent-1-ene-1-sulfonyl)-pyrido[3,4-d]pyrimidin-4-yl}-amine;

(3-Chloro-4-fluoro-phenyl)-(6-ethenesulfinyl-pyrido[3,4-d]pyrimidin-4-yl]-amine;

3-[4-(1-Phenyl-ethylamino)-quinazolin-6-ylcarbamoyl]-acrylic acid2-morpholin-4-yl-ethyl ester;

But-2-enedioic acid(4-imidazol-1-yl-butyl)-amide[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

4-[4-(1-Phenyl-ethylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoic acid3-diethylamino-propyl ester;

Pent-2-enedioic acid 5-{[2-(4-methyl-piperazin-1-yl)-ethyl]-amide}1-{[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide};

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

7-Imidazol-1-yl-hept-2-ynoicacid[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-amide;

But-2-enedioicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-dimethylamino-propyl)-amide;

But-2-enedioicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;

4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-hept-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Dimethylamino-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

5-(4-Methyl-piperazin-1-yl)-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-(4-methyl-piperazin-1-yl)-ethyl ester;

4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-imidazol-1-yl-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide];

Pent-2-enedioic acid1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];

4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-morpholin-4-yl-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-{[3-(4-methyl-piperazin-1-yl)-propyl]-amide};

(3-Bromo-phenyl)-{6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;

(3-Bromo-phenyl)-(6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl}-pyrido[3,4-d]pyrimidin-4-yl)-amine;

(3-Bromo-phenyl)-[6-(5-morpholin-4-yl-pent-1-ene-1-sulfonyl)-pyrido[3,4-d]pyrimidin-4-yl]-amine;

(3-Bromo-phenyl)-(6-ethenesulfinyl-pyrido[3,4-d]pyrimidin-4-yl)-amine;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide(3-dimethylamino-propyl)-amide;

But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;

4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

5-Dimethylamino-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

5-(4-Methyl-piperazin-1-yl)-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide;

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide];

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];

4-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoicacid 2-morpholin-4-yl-ethyl ester;

Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-amide}5-{[3-(4-methyl-piperazin-1-yl)-propyl]-amide};

(3-Chloro-4-fluoro-phenyl)-(6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl]-quinazolin-4-yl)-amine;

(3-Chloro-4-fluoro-phenyl)-(6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl}-quinazolin-4-yl)-amine;

But-2-enedioicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide(3-dimethylamino-propyl)-amide;

But-2-enedioicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;

4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

7-Dimethylamino-hept-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

5-Dimethylamino-pent-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

5-(4-Methyl-piperazin-1-yl)-pent-2-ynoicacid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide;

4-[4-(3-Bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoic acid2-(4-methyl-piperazin-1-yl)-ethyl ester;

4-[4-(3-Bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoic acid2-imidazol-1-yl-ethyl ester;

Pent-2-enedioic acid 1-{[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide];

Pent-2-enedioic acid 1-{[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];

4-[4-(3-Bromo-phenylamino)-quinazolin-6-ylcarbamoyl]-but-3-enoic acid2-morpholin-4-yl-ethyl ester;

Pent-2-enedioic acid 1-{[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide}5-{[3-(4-methyl-piperazin-1-yl)-propyl]-amide};

3-[4-(1-Phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-acrylicacid 2-morpholin-4-yl-ethyl ester;

But-2-enedioic acid(4-imidazol-1-yl-butyl)-amide[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

4-[4-(1-Phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 3-diethylamino-propyl ester;

Pent-2-enedioic acid 5-{[2-(4-methyl-piperazin-1-yl)-ethyl]-amide}1-{[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide};

4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

7-Imidazol-1-yl-hept-2-ynoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

6-Dimethylamino-hex-2-ynoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;

But-2-endioicacid[4-(3-chloro-4-fluorophenylamino)-7-fluoroquinazolin-6-yl]amide(3-dimethylaminopropyl)amide;

But-2-endioicacid[7-chloro-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl]amide(3-dimethylaminopropyl)amide;

N-[4-[3-(Bromophenyl)amino]-5-fluoro-7-[3-(4-morpholino)propoxy]quinazolin-6-yl]acrylamide;and

N-[4-[(3-(Chloro-4-fluorophenyl)amino]-5-fluoro-7-(1,N-imidazoyl)propoxy]quinazolin-6-yl]acrylamide.

BIOLOGICAL METHODS

Tissue Culture

A431 human epidermoid carcinoma cells were obtained from the AmericanType Culture Collection, Rockville, Md. and maintained as monolayers indMEM (Dulbecco's modified eagle medium)/F12, 50:50 (Gibco/BRL)containing 10% fetal bovine serum. For growth inhibition assays,dilutions of the designated compound in 10 μL were placed in 24-wellLinbro plates (1.7×1.6 cm, flat bottom) followed by the addition ofcells (2×10⁴) in 2 mL of media. The plates were incubated for 72 hoursat 37° C. in a humidified atmosphere containing 5% CO₂ in air. Cellgrowth was determined by cell count with a Coulter Model AM electroniccell counter (Coulter Electronics, Inc., Hialeah, Fla.).

Purification of Epidermal Growth Factor Receptor Tyrosine Kinase

Human EGF receptor tyrosine kinase was isolated from A431 humanepidermoid carcinoma cells by the following method. Cells were grown inroller bottles in dMEM/F12 media (Gibco/BRL) containing 10% fetal calfserum. Approximately 10⁹ cells were lysed in 2 volumes of buffercontaining 20 mM N-[2-hydroxyethyl]-piperazine-N′-[2-ethane sulfonicacid] (Hepes), pH 7.4, 5 mM ethylene glycol-bis(β-aminoethyl ether) N,N, N′, N′-tetraacetic acid (EGTA), 1% Triton X-100, 10% glycerol, 0.1 mMsodium orthovanadate, 5 mM sodium fluoride, 4 mM pyrophosphate, 4 mMbenzamide, 1 mM dithiothreitol (DTT), 80 μg/mL aprotinin, 40 μg/mLleupeptin, and 1 mM phenylmethyl sulfonyl fluoride (PMSF). Aftercentrifugation at 25,000×g for 10 minutes, the supernatant was appliedto a fast Q sepharose column (Pharmacia Biotech., Inc., Piscataway,N.J.) and eluted with a linear gradient from 0.1 M NaCl to 0.4 M NaCl in50 mM Hepes, 10% glycerol, pH 7.4. Enzyme active fractions were pooled,divided into aliquots, and stored at −100° C. Fibroblast growth factorreceptor (FGFR), platelet-derived growth factor (PDGF), insulin, andc-src tyrosine kinases were obtained by methods well-known in the art.For example, see Fry, et al., “Strategies For The Discovery Of NovelTyrosine Kinase Inhibitors With Anticancer Activity, Anticancer DrugDesign, 1994;9:331-351.

Tyrosine Kinase Assays

Enzyme assays for IC₅₀ determinations were performed in 96 well filterplates (Millipore MADVN6550, Millipore, Bedford, Mass.). The totalvolume was 0.1 mL containing 20 mM Hepes, pH 7.4, 50 μM sodium vanadate,40 mM magnesium chloride, 10 μM adenosine triphosphate (ATP) containing0.5 μCi of [³²P]ATP, 20 μg of poly Glutamic acid/tyrosine (SigmaChemical Co., St. Louis, Mo.), 10 ng of EGF receptor tyrosine kinase andappropriate dilutions of inhibitor. All components except the ATP areadded to the well and the plate incubated with shaking for 10 minutes at25° C. The reaction is started by adding [³²P]ATP, and the plate isincubated at 25° C. for 10 minutes. The reaction is terminated byaddition of 0.1 mL of 20% trichloroacetic acid (TCA). The plate is keptat 4° C. for at least 15 minutes to allow the substrate to precipitate.The wells are then washed 5 times with 0.2 mL of 10% TCA and ³²Pincorporation determined with a Wallac beta plate counter (Wallac, Inc.,Gaithersburg, Pa.). Assays using intracellular kinase domains of PDGF,FGF, and insulin receptors, as well as those for c-src, were performedas described for the EGF receptor except that 10 mM Manganese chloridewas included in the reaction.

Western Blotting Procedure

Extracts were made by lysing the monolayers in 0.2 mL of boiling Laemllibuffer (2% sodium dodecyl sulfate, 5% beta-mercaptoethanol, 10% glyceroland 50 mM tris[hydroxymethyl]aminomethane (Tris), pH 6.8), and thelysates were heated to 100° C. for 5 minutes. Proteins in the lysatewere separated by polyacrylamide gel electrophoresis andelectrophoretically transferred to nitrocellulose. The membrane waswashed once in 10 mM Tris, pH 7.2, 150 mM NaCl, 0.01% Azide (TNA), andblocked overnight in TNA containing 5% bovine serum albumin and 1%ovalbumin. The membrane was blotted for 2 hours with antiphosphotyrosineantibody (UBI, 1 μg/mL in blocking buffer) and then washed twice in TNA,once in TNA containing 0.05% Tween-20 detergent and 0.05% nonidet P-40detergent and twice in TNA. The membranes were then incubated for 2hours in blocking buffer containing 0.1 μCi/mL of [¹²⁵I]protein A andthen washed again as above. After the blots were dry, they were loadedinto a film cassette and exposed to X-AR X-ray film (Eastman Kodak Co.,Rochester, N.Y.) for 1 to 7 days. Band intensities were determined witha Molecular Dynamics laser densitometer.

Autophosphorylation Assay

A431 human epidermoid carcinoma cells were grown in 6-well plates toabout 80% confluency and then incubated in serum-free media for 18hours. Duplicate sets of cells were treated with a range ofconcentrations of the designated compound to be tested as an inhibitorfor 15 minutes. The cells were then stimulated with 100 ng/mL of EGF for5 minutes and extracts made as described under the Western BlottingProcedure.

Irreversibility Test Protocol

A431 human epidermoid carcinoma cells were grown in 6-well plates toabout 80% confluency and then incubated in serum-free media for 18hours. Duplicate sets of cells were treated with 2 μM of designatedcompound to be tested as an irreversible inhibitor for either 1 or 2hours. One set of cells was then stimulated with 100 ng/mL of EGF for 5minutes and extracts made as described under the western blottingprocedure. The other set of cells were washed free of the compound withwarmed serum-free media, incubated for 2 hours, washed again, incubatedanother 2 hours, washed again, and then incubated a further 4 hours.This set of cells was then stimulated with EGF and extracts made similarto the first set of cells.

Results

Table 1 shows the IC₅₀ values of various compounds for inhibition of theisolated EGF receptor tyrosine kinase in the first column, and forinhibition of EGF-stimulated autophosphorylation of the EGF-receptor inA431 cells in the second column. Most compounds of the current inventioninhibited the isolated enzyme with low nanomolar or subnanomolar potencyand the majority had low nanomolar potency when inhibiting cellularautophosphorylation. Table 2 indicates the ability of A431 cells torecover EGF receptor autophosphorylation activity after completesuppression of the enzyme by these compounds followed by their removalfrom the medium. The first set of cell extracts (2nd column) shows thatmany of the compounds tested completely suppressed EGF receptorautophosphorylation after the initial 2 hour incubation. The thirdcolumn in Table 2 shows the percent return of EGF receptorautophosphorylation activity after the washes and incubation incompound-free medium as described in the methods. At least 30 of thecompounds retained 50% or greater inhibition of kinase activity afterthis treatment with at least 23 of the compounds showing 90%-100%inhibition of the original enzyme activity. Cells treated with all othercompounds tested were able to recover 86% to 100% of their EGF-dependentautophosphorylation activity. Reversibility studies where the incubationtime was carried out further indicate that the time required for returnof 50% of the activity was 21 hours (Table 3). A specific sidechainrequirement for irreversible interaction is illustrated by the fact thatCompound 9, a very close analog of Compound 3 with equally potentinhibitory activity against the enzyme, was completely reversible.Furthermore the requirement for a conjugated alkene in the sidechain isdemonstrated by comparing Compounds 3 and 11 with their saturatedanalogues 17 and 28. In these cases the compounds all show similarpotency against the isolated enzyme and are not well differentiated inthe autophosphorylation assay, but Compounds 17 and 28 have noinhibitory effect at the end of 8 hours washoff, whereas theirreversible inhibitors Compounds 3 and 11 have 89% and 100% inhibitionof the enzyme at that time.

Table 4 illustrates that Compound 3 retains very high specificity forthe EGF receptor tyrosine kinase as opposed to other tyrosine kinaseenzymes and indicates that the active sidechain in Example 3 does notindiscriminately interact with other enzymes.

Finally, Compound 3 was tested for its ability to inhibit proliferationin A431 human epidermoid carcinoma cells. An IC₅₀ of 0.30±0.09micromolar was obtained indicating its ability to stop tumor growth.

The properties of an irreversible inhibitor are attractive because itwould help circumvent or solve the potential problems of a short plasmahalf-life and/or a requirement for prolonged suppression of its target.One bolus injection at an appropriate dose of an irreversible inhibitorwould in effect be enough to abolish the existing target activity, andthe return of that activity would be dependent on the rate ofresynthesis of the target. Since it is known that the half-life forturnover of the EGF receptor is 20 hours in A431 cells, an inhibitorcould keep the receptor suppressed with administration once or twice aday. This eliminates the need for multiple injections, or the use ofinfusion or osmotic pumps. Alternatively, it can allow for lower dosesto be used in multiple or continuous dosing regimens to achieve resultswith an irreversible inhibitor, as the receptor activity is no longerbeing repressed under equilibrium binding conditions.

TABLE 1 IC₅₀S OF EXAMPLES AGAINST ISOLATED EGFR KINASE ACTIVITY AND EGFRAUTOPHOSPHORYLATION IN A431 CELLS EGFR Tyrosine Autophos- Kinasephorylation Example IC₅₀ (nM) IC₅₀ (nM) 2 2.7 156 3 0.36 14 4 89 2090 511 6 104 7 27 130 8 0.029 13 9 0.46 20 11 0.84 2.7 12 910 >10000 13 1.690 14 0.25 53 15 1.2 16 16 3.7 2450 17 1.9 60 18 1.6 2.3 19 0.42 4.7 200.91 4.5 21 3.6 5.3 22 1.5 27 23 2 18 24 4 7.9 25 3 21 26 1.7 3 27 3.3194 28 0.52 15 29 1.2 28 30 1.4 2.7 31 0.55 8.7 32 1.75 35 33 0.89 10 340.47 5.5 35 0.54 108 36 0.91 3.4 37 0.48 8.3 38 0.17 13 39 1.6 44 400.76 2.4 41 1.1 5.6 42 23 173 43 1.4 24 44 21 327 45 1.6 1039 46 1.2 12047 2.7 67 48 1.1 27 49 4.2 2280 50 0.5 7.7 51 9.1 77 52 0.69 20 53 0.8152 54 2.4 108 55 0.37 >500 56 0.44 59 57 0.43 >500 58 124 >500

TABLE 2 RECOVERY OF EGF RECEPTOR AUTOPHOSPHORYLATION ACTIVITY IN A431CELLS AFTER EXPOSURE TO 2 μM INHIBITOR % Control % Control After After 8Hours in Example 2-Hour Drug-Free Media No. Incubation IncubationIrreversible 2 0 92 N 3 1 13 Y 4 55 98 N 5 N 6 N 7 N 8 0 95 N 9 0 99 N11 0 0 Y 12 85 100 N 13 1 90 N 14 0 50 Y 15 0 85 N 16 30 85 N 17 0 100 N18 0 0 Y 19 0 0 Y 20 0 0 Y 21 0 0 Y 22 0 0 Y 23 0 0 Y 24 0 0 Y 25 0 0 Y26 0 0 Y 27 0 96 N 28 0 100 N 29 0 100 N 30 0 0 Y 31 0 35 Y 32 0 0 Y 330 0 Y 34 0 0 Y 35 0 20 Y 36 0 0 Y 37 0 0 Y 38 0 0 Y 39 0 80 N 40 0 0 Y41 0 0 Y 42 12 50 Y 43 0 0 Y 44 13 42 Y 45 0 21 Y 46 19 59 Y 47 0 26 Y48 0 53 Y 49 50 75 N 50 0 32 Y 51 12 32 Y 52 0 0 Y 53 0 0 Y 54 0 3 Y 5532 32 Y 56 0 0 Y 57 43 39 Y 58 81 95 N

TABLE 3 REVERSIBILITY OF EGF RECEPTOR AUTOPHOSPHORYLATION INHIBITOR INA431 CELLS TREATED FOR 2 HOURS WITH 2 μM OF COMPOUND 3 OR COMPOUND 9INHIBITOR Compound 3 Compound 9 Hours in % of Control % of ControlDrug-Free Autophos- Autophos- Media phorylation phorylation 0 0 4 4 1224 8 23 100 23 54 100

TABLE 4 EFFECT OF EXAMPLE 3 ON INHIBITION OF DIFFERENT TYROSINE KINASESIC₅₀ (nM) EGFR C-SRC Insulin PDGF FGF1 0.36 >2,500 >50,000 >50,000>50,000

In Vivo Data

Female nude mice (NCr nu/nu, Taconic Farms) 18-20 g were implanted SCwith tumor fragments (approximately 30 mg) in the region of the rightaxilla on Day 0. The tumor used in this study was an NIH 3T3 fibroblasttransfected with the h-EGF receptor (Decker, et al., J Biol Chem,1990;265:7009-7015). This model is very tumorigenic, producing a 100%take rate, and doubles in volume in less than 2 days. The compound ofExample 3 was administered intraperitoneally every 12 hours on Days 3through 7 for a total of 10 injections (5 mice per group). The vehiclewas 6% dimethyl acetamide in 50 mM lactate buffer, pH 4.0. Tumor volumeswere recorded three times per week by measuring the length and width ofthe individual tumors and calculating the mass in milligrams accordingto the formula (a×b²)/2, where a and b are the length and width of thetumor. Percent T/C (treated/control) was calculated based on the ratioof the median tumor volume of the treated tumors compared with themedian tumor volume of the control tumors on specified measurement days.

Treatment at both 100 and 30 mg/kg/injection inhibited tumor growth by40% to 50% as assessed on Days 7, 10, and 12 of the experiment. Noactivity was observed at 10 or 3 mg/kg/injection. No weight loss,lethality, or clinical signs of toxicity were observed at any doselevel.

% T/C Day Group 7 10 12 Control 100 100 100 Example No. 3 @ 100(mg/kg/injection) 57 70 57 Example No. 3 @ 30 (mg/kg/injection) 48 66 53Example No. 3 @ 3 (mg/kg/injection) 115 138 113

Additional In Vivo Testing

Using a similar protocol to that described above, with the exceptionthat six mice per group are used, and the dosing schedules are asdescribed, several compounds have been tested against a variety of tumorxenografts. These include the h-EGF receptor transfected NIH3T3-transfected fibroblast model described above; the A431 humanepidermoid carcinoma, which heavily overexpresses the EGF receptor; theMCF7 human breast carcinoma, which is sensitive to EGF receptorinhibitors and known to express the EGF receptor and erbB-2 and erbB-3;the SK-OV-3 human ovarian carcinoma, which greatly overexpresses erbB-2:the AH-125 small cell lung cancer which overexpresses the EGF receptor;and the murine 16/c mammary adenocarcinoma.

Example 3 EGFR Tumor

IP Dosing Bid Days 3 Through 7

@100 mg/kg produced 4 day growth delay.

@30 mg/kg produced 2.5 day growth delay.

IP Dosing Bid Days 1 Through 13

@300 mg/kg no activity.

@190 and 120 mg/kg 1 day growth delay.

@75 mg/kg 5 day growth delay.

Example 11 MCF-7 Tumor

IP Dosing Bid Days 1-5, 8-12, 15-19

@47 mg/kg 17.4 day growth delay.

@28 mg/kg 22.9 day growth delay.

Murine 16/c Mammary Adenocarcinoma

Inactive at doses of up to 120 mg/kg bid.

EGFR Tumor

IP Dosing Bid for 14 Days

@75 mg/kg produced 8.7 day growth delay.

@47 mg/kg 6.6 day growth delay.

@29 mg/kg 2.3 day growth delay.

@18 mg/kg 1.8 day growth delay.

@150 mg/kg toxic.

@75 mg/kg toxic.

IP Dosing Bid Days 3-7, 10-14, 17-21, 24-28

@75 mg/kg 19.9 day growth delay.

@150 mg/kg toxic.

IP Dosing Once Daily Days 3-17

@75 mg/kg 11.7 day growth delay.

IP Dosing Once Daily Days 3-7, 10-14, 17-21

@75 mg/kg 5.3 day growth delay.

@150 mg/kg toxic.

A431 Tumor

IP Dosing Bid Days 7-11, 4-18, 21-25

@28 mg/kg produced a 28.2 day growth delay.

PO Dosing Once Daily Days 7-21

@200 mg/kg produced a 3.5 day growth delay.

@100 mg/kg a 2 day growth delay.

SK-OV-3 Tumor

ID Dosing Bid Days 10-14, 17-21, 24-28

@30 mg/kg produced 1.2 day growth delay.

Example 19 EGFR Tumor

IP Dosing Bid for 14 Days

@124 mg/kg produced 11.8 day growth delay.

@77 mg/kg 7.9 day growth delay.

@48 mg/kg 6.4 day growth delay.

@200 mg/kg toxic.

SK-OV-3 Tumor

ID Dosing Bid Days 10-14, 17-21, 24-28

@30 mg/kg produced 1.3 day growth delay.

A431 Tumor

SC-Infusion (Alzet) Days 9-23

@24 mg/kg/day produced a 14 day growth delay.

@12 mg/kg/day produced a 15 day growth delay.

Example 21

IP Dosing Bid

@48 mg/kg toxic.

EGFR Tumor

IP Dosing Bid for 14 Days

@12.5 mg/kg produced 16.8 day growth delay.

@6.25 mg/kg 9.3 day growth delay.

@25 mg/kg toxic.

SC-Infusion (Alzet)

@200, 124, 77, and 48 mg/kg/day toxic.

AH-125 Tumor

SC-Infusion (Alzet) Days 19-33

@20.6 mg/kg/day produced a 10.0 day growth delay.

@10.4 mg/kg/day produced a 9.5 day growth delay.

@5.5 mg/kg/day produced a 9.5 day growth delay.

A431 Tumor

SC-Infusion (Alzet) Days 9-23, 42-56

@48 mg/kg/day produced a 55 day growth delay.

@24 mg/kg/day produced a 60 day growth delay.

@12 mg/kg/day produced a 51 day growth delay.

Example 36 EGFR Tumor

IP Dosing Bid for 7 Days

@48 mg/kg produced 10.3 day growth delay.

IP Dosing Bid for 14 Days

@25 mg/kg produced 8.7 day growth delay.

@12.5 mg/kg 3.5 growth delay.

@50 mg/kg toxic.

SC-Infusion (Alzet)

@200, 124, 77 mg/kg/day toxic.

Example 40

IP Dosing Bid

@48 and 20 mg/kg toxic.

EGFR Tumor

Inefficacious 10 and 5 mg/kg bid for 14 days.

SC-Infusion (Alzet)

@200, 124, 77, and 48 mg/kg/day toxic.

What is claimed is:
 1. A compound having the Formula II

wherein Q is

X is —D—E—F and Y is —SR⁴, —OR⁴, —NHR³ or hydrogen, or X is —SR⁴, —OR⁴,—NHR³ or hydrogen, and Y is —D—E—F; D is

 or absent;

 provided that when E is

 D is not

 R¹ is hydrogen, halogen, or C₁-C₆ alkyl; R², R³, and R⁴ areindependently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)—N-piperidinyl,—(CH₂)_(n)—N-piperazinyl, —(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl],—(CH₂)_(n)—N-pyrrolidyl, —(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl,—(CH₂)_(n)-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino, —(CH₂)_(n)—N-hexahydroazepine orsubstituted C₁-C₆ alkyl, wherein the substituents are selected from —OH,—NH₂, or

 A and B are independently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄-(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)—N-pyridyl, —(CH₂)_(n)-imidazoyl or —(CH₂)_(n)—N-imidazoyl;E¹, E², and E³ are independently halogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₁-C₆ alkoxy, C₃-C₈ cycloalkoxy, nitro, C₁-C₆ perfluoroalkyl, hydroxy,C₁-C₆ acyloxy, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —NH(C₃-C₈cycloalkyl), —N(C₃-C₈ cycloalkyl)₂, hydroxymethyl, C₁-C₆ acyl, cyano,azido, C₁-C₆ thioalkyl, C₁-C₆ sulfinylalkyl, C₁-C₆ sulfonylalkyl, C₃-C₈thiocycloalkyl, C₃-C₈ sulfinylcycloalkyl, C₃-C₈ sulfonylcycloalkyl,mercapto, C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkoxycarbonyl, C₂-C₄alkenyl, C₄-C₈ cycloalkenyl, or C₂-C₄ alkynyl; and R⁵ is hydrogen,halogen, C₁-C₆-perfluoroalkyl, 1,1-difluoro(C₁-C₆)alkyl, C₁-C₆ alkyl,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)-piperazinyl,—(CH₂)_(n)-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)-N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino,

 —CH═CH—(C₁-C₆)alkyl, —(CH₂)_(n)—N-hexahydroazepine, —(CH₂)_(n)NH₂,—(CH₂)_(n)NH(C₁-C₆ alkyl), —(CH₂)_(n)N(C₁-C₆ alkyl)₂,-1-oxo(C₁-C₆)alkyl, carboxy, (C₁-C₆)alkyloxycarbonyl,N—(C₁-C₆)alkylcarbamoyl, phenyl or substituted phenyl, wherein thesubstituted phenyl can have from one to three substituents independentlyselected from Z¹, z², Z³ or a monocyclic heteroaryl group, and eachC₁-C₆ alkyl group can be substituted with —OH, —NH₂ or —NAB, where A andB are as defined above, R⁶ is hydrogen or C₁-C₆ alkyl; and n is 1 to 4,p is 0 or 1, and the pharmaceutically acceptable salts, esters, andamides thereof.
 2. A compound of claim 1 wherein E¹ and E² are hydrogen,and E³ is a halogen.
 3. A compound of claim 2 wherein the halogen isbromine.
 4. A compound of claim 3 wherein the bromine is located at the3 or meta position of the phenyl ring.
 5. A compound of claim 1 whereinQ is


6. A compound of claim 1 wherein Q is


7. A compound of claim 1 wherein Q is


8. A compound of claim 6 wherein X is


9. A compound of claim 7 wherein X is


10. A compound of claim 7 wherein X is


11. A compound of claim 5 wherein X is

and Y is hydrogen.
 12. A compound of claim 1 wherein E¹ is hydrogen, E²is fluorine, and E³ is chlorine.
 13. A compound of claim 12 wherein thefluorine is located at the 4 position and the chlorine is located at the3 position of the phenyl ring.
 14. A compound according to claim 1wherein X is —D—E—F and F is

and R⁵ is 1,1-difluoro(C₁-C₆)alkyl, C₁-C₆alkyl,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)-piperazinyl,—(CH₂)_(n)-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino, —CH═CH—(C₁-C₆)alkyl,—(CH₂)_(n)—N-hexahydroazepine, —(CH₂)_(n)NH₂, —(CH₂)_(n)NH(C₁-C₆ alkyl),—(CH₂)_(n)N(C₁-C₆ alkyl)₂, -1-oxo(C₁-C₆)alkyl, carboxy,(C₁-C₆)alkyloxycarbonyl, N—(C₁-C₆)alkylcarbamoyl, and each C₁-C₆ alkylgroup of 1,1-difluoro(C₁-C₆)alkyl, C₁-C₆ alkyl, —CH═CH—(C₁-C₆)alkyl,-1-oxo(C₁-C₆)alkyl, (C₁-C₆)alkyloxycarbonyl, or —N—(C₁-C₆)alkylcarbamoylis substituted with —OH, —NH₂, or —NAB, where A and B are as definedabove; or Y is —D—E—F and F is

and R⁵ is 1,1-difluoro(C₁-C₆)alkyl, C₁-C₆alkyl,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)-piperazinyl,—(CH₂)_(n)-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino, —CH═CH—(C₁-C₆)alkyl,—(CH₂)_(n)—N-hexahydroazepine, —(CH₂)_(n)NH₂, —(CH₂)_(n)NH(C₁-C₆ alkyl),—(CH₂)_(n)N(C₁-C₆ alkyl)₂, -1-oxo(C₁-C₆)alkyl, carboxy,(C₁-C₆)alkyloxycarbonyl, N—(C₁-C₆)alkylcarbamoyl, and each C₁-C₆ alkylgroup of 1,1-difluoro(C₁-C₆)alkyl, C₁-C₆ alkyl, —CH═CH—(C₁-C₆)alkyl,-1-oxo(C₁-C₆)alkyl, (C₁-C₆)alkyloxycarbonyl, or —N—(C₁-C₆)alkylcarbamoylis substituted with —OH, —NH₂, or —NAB, where A and B are as definedabove.
 15. A compound according to claim 1 wherein X is —D—E—F; Y is—SR⁴, —OR⁴, or —NHR³; and R³ and R⁴ are —(CH₂)_(n)—N-piperidinyl,—(CH₂)_(n)—N-piperazinyl, —(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl],—(CH₂)_(n)—N-pyrrolidyl, —(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl,—(CH₂)_(n)-imidazoyl, —(CH₂)_(n)—N-morpholino,—(CH₂)_(n)—N-thiomorpholino, —(CH₂)_(n)—N-hexahydroazepine orsubstituted C₁-C₆ alkyl, wherein the substituents are selected from —OH,—NH₂, or

 A and B are independently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)—N-pyridyl, —(CH₂)_(n)-imidazoyl or —(CH₂)_(n)—N-imidazoyl; orY is —D—E—F; X is —SR⁴, —OR⁴, or NHR³; and R³ and R⁴ are—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)-pyridinyl, —(CH₂)_(n)—N-imidazoyl, —(CH₂)_(n)-imidazoyl,—(CH₂)_(n)—N-morpholino, —(CH₂)_(n)—N-thiomorpholino,—(CH₂)_(n)—N-hexahydroazepine or substituted C₁-C₆ alkyl, wherein thesubstituents are selected from —OH, —NH₂, or

 A and B are independently hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)—N-piperidinyl, —(CH₂)_(n)—N-piperazinyl,—(CH₂)_(n)—N₁-piperazinyl[N₄—(C₁-C₆)alkyl], —(CH₂)_(n)—N-pyrrolidyl,—(CH₂)_(n)—N-pyridyl, —(CH₂)_(n)-imidazoyl, or —(CH₂)_(n)—N-imidazoyl.16. The compounds:N-[4-(3-Bromo-phenylamino)-pyrido[4,3-d]pyrimidin-7-yl]-acrylamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide;N-[4-(3-Methyl-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-methylacrylamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-methacrylamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-ethenylsulfonamide;N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3,2-d]pyrimidin-8-yl]acrylamide;N-[4-(3-Bromo-phenylamino)-benzo-[b]thieno[3,2-d]pyrimidin-6-yl]acrylamide;N-[4-(3-Bromo-phenylamino)-benzo[b]thieno[3,2-d]pyrimidin-7-yl]acrylamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]penta-2,4-dienamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]E-but-2-enamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]cinnamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-E,3-chloroacrylamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-propynamide;4-[(3-Bromo-phenyl)amino]-6-(ethenesulfonyl)pyrido-[3,4-d]pyrimidine;MethylN-[4-[(3-bromophenyl)amino]-P-ethenyl-pyrido[3,4-d]pyrimidin-6-yl]phosphonamidate;N-[1-(3-Bromo-phenylamino)-9H-2,4,9-triaza-fluoren-7-yl]-acrylamide;N-[4-(3-Bromo-phenylamino)-9H-1,3,9-triaza-fluoren-6-yl]-acrylamide;N-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-acrylamide;N-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-methyl-acrylamide;(3-Chloro-4-fluoro-phenyl)-(6-ethenesulfinyl-pyrido[3,4-d]pyrimidin-4-yl]-amine;(3-Bromo-phenyl)-(6-ethenesulfinyl-pyrido[3,4-d]pyrimidin-4-yl)-amine;N-[4-(3-Bromo-phenylamino)-pyrido[4,3-d]-pyrimidin-7-yl]-N-(3-morpholin-4-yl-propyl)-acrylamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]-pyrimidin-6-yl]-N-(3-morpholin-4-yl-propyl)-acrylamide;N-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-N-(2-(N,N-dimethylamino)ethyl)acrylamide;N-[4-(3-Bromo-phenylamino)-7-(3-morpholin-4-yl-propoxy)-pyrido[3,2-d]pyrimidin-6-yl]-acrylamide; But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-dimethylamino-propyl)-amide; But-2-enedioicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide(3-imidazol-1-yl-propyl)-amide;4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;6-Dimethylamino-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;7-Dimethylamino-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;5-Dimethylamino-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;5-(4-Methyl-piperazin-1-yl-pent-2-ynoicacid[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-(4-methyl-piperazin-1-yl)-ethyl ester;4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-(imidazol-1-yl)-ethyl ester; Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide]; Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];4-[4-(3-Chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-morpholin-4-yl-ethyl ester; Pent-2-enedioic acid1-{[4-(3-chloro-4-fluoro-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-{[3-4-methyl-piperazin-1-yl)-propyl]-amide};(3-Chloro-4-fluoro-phenyl)-{6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl]-pyrido[3,4-d]pyrimidin-4-yl}amine;(3-Chloro-4-fluoro-phenyl)-(6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl}-pyrido[3,4-d]pyrimidin-4-yl)-amine;4,4-Difluoro-8-morpholin-4-yl-oct-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;8-Dimethylamino-4,4-difluoro-oct-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;6-Dimethylamino-hex-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;6-Morpholin-4-yl-hex-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;7-Dimethylamino-hept-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;7-Morpholin-4-yl-hept-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;5-Dimethylamino-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;5-Morpholin-4-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;5-Imidazol-1-yl-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;5-(4-Methyl-piperazin-1-yl)-pent-2-ynoicacid[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-(4-methyl-piperazin-1-yl)-ethyl ester;4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-imidazol-1-yl-ethyl ester; Pent-2-enedioic acid1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-morpholin-4-yl-propyl)-amide]; Pent-2-enedioic acid1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-[(3-diethylamino-propyl)-amide];4-[4-(3-Bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 2-morpholin-4-yl-ethyl ester; Pent-2-enedioic acid1-{[4-(3-bromo-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide}5-{[3-(4-methyl-piperazin-1-yl)-propyl]-amide};(3-Bromo-phenyl)-6-[2-(3-dimethylamino-propoxy)-ethenesulfonyl]-pyrido[3,4-d]pyrimidin-4-yl}-amine;(3-Bromo-phenyl)-(6-{2-[4-(4-methyl-piperazin-1-yl)-butylamino]-ethenesulfonyl}-pyrido[3,4-d]pyrimidin-4-yl)-amine;(3-Bromo-phenyl)-[6-(5-morpholin-4-yl-pent-1-ene-1-sulfonyl)-pyrido[3,4-d]pyrimidin-4-yl]-amine;3-[4-(1-Phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-acrylicacid 2-morpholin-4-yl-ethyl ester; But-2-enedioicacid(4-imidazol-1-yl-butyl)-amide[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;4-[4-(1-Phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-ylcarbamoyl]-but-3-enoicacid 3-diethylamino-propyl ester; Pent-2-enedioic acid5-{[2-(4-methyl-piperazin-1-yl)-ethyl]-amide}1-{[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide};4,4-Difluoro-7-morpholin-4-yl-hept-2-enoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;7-Dimethylamino-4,4-difluoro-hept-2-enoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;7-Imidazol-1-yl-hept-2-ynoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide;(3-Chloro-4-fluoro-phenyl)-[6-(5-morpholin-4-yl-pent-1-ene-1-sulfonyl)-pyrido[3,4-d]pyrimidin-4-yl]-amine;and 6-Dimethylamino-hex-2-ynoicacid[4-(1-phenyl-ethylamino)-pyrido[3,4-d]pyrimidin-6-yl]-amide.
 17. Apharmaceutically acceptable composition that comprises a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 18. A method oftreating cancer wherein an epidermal growth factor receptor tyrosinekinase is abnormally active, the method comprising administering to apatient having said cancer a therapeutically effective amount of acompound of claim
 1. 19. A method of treating restenosis, the methodcomprising administering to a patient having restenosis or at risk ofhaving restenosis a therapeutically effective amount of a compound ofclaim
 1. 20. A method of irreversibly inhibiting tyrosine kinases, themethod comprising administering to a patient in need of tyrosine kinaseinhibition a tyrosine kinase inhibiting amount of a compound of claim 1.21. A method of treating psoriasis, the method comprising administeringto a patient having psoriasis a therapeutically effective amount of acompound of claim
 1. 22. A method of treating atherosclerosis, themethod comprising administering to a patient having atherosclerosis atherapeutically effective amount of a compound of claim
 1. 23. A methodof treating endometriosis, the method comprising administering to apatient having endometriosis a therapeutically effective amount of acompound of claim 1.